Handbook of Clinical Neurology, Vol.

153 (3rd series)

Human Prion Diseases
M. Pocchiari and J. Manson, Editors
https://doi.org/10.1016/B978-0-444-63945-5.00016-7
Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 16

Prion-like mechanisms in Alzheimer disease

LARY C. WALKER*
Department of Neurology and Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States

Abstract
Senile plaques and neurofibrillary tangles are the principal histopathologic hallmarks of Alzheimer dis-
ease. The essential constituents of these lesions are structurally abnormal variants of normally generated
proteins: Ab protein in plaques and tau protein in tangles. At the molecular level, both proteins in a path-
ogenic state share key properties with classic prions, i.e., they consist of alternatively folded, b-sheet-rich
forms of the proteins that autopropagate by the seeded corruption and self-assembly of like proteins. Other
similarities with prions include the ability to manifest as polymorphic and polyfunctional strains, resistance
to chemical and enzymatic destruction, and the ability to spread within the brain and from the periphery to
the brain. In Alzheimer disease, current evidence indicates that the pathogenic cascade follows from the
endogenous, sequential corruption of Ab and then tau. Therapeutic options include reducing the produc-
tion or multimerization of the proteins, uncoupling the Ab–tauopathy connection, or promoting the inac-
tivation or removal of anomalous assemblies from the brain. Although aberrant Ab appears to be the prime
mover of Alzheimer disease pathogenesis, once set in motion by Ab, the prion-like propagation of tauo-
pathy may proceed independently of Ab; if so, Ab might be solely targeted as an early preventive measure,
but optimal treatment of Alzheimer disease at later stages of the cascade could require intervention in both
pathways.

ALZHEIMER DISEASE with an ever greater burden of caring for afflicted persons
falling on younger generations. Disease-modifying treat-
Epidemiology, signs, and symptoms
ments are urgently needed, but these can only emerge from
One of the most feared hazards of growing old is the pro- a deep understanding of AD itself. A defining pathologic
found deterioration of mental faculties known as dementia. feature of AD is the abnormal accumulation in the brain
More than 50 different conditions are associated with of two proteins, Ab and tau; recent evidence shows that
dementia (Vonsattel and Hedley-White, 2001), but of these, this process is initiated and sustained by a prion-like mech-
Alzheimer disease (AD) is the most common, with a world- anism of seeded protein aggregation.
wide prevalence in 2010 of approximately 35 million Symptomatically, AD typically begins with the grad-
people (Dartigues, 2009; Holtzman et al., 2011; Reitz ual onset of mild cognitive impairment, progressing
et al., 2011). The incidence and prevalence of AD double inexorably to dementia with an average clinical duration
every 5 years between the ages of 65 and 95 (Kawas of 7–10 years (Holtzman et al., 2011) (although the time
and Katzman, 1999). As the average life expectancy of course is variable). The signs and symptoms shown by
populations grows in many parts of the world, and in the individual patients also can vary substantially, but the
absence of an effective prevention or treatment, as many diagnosis of AD is established by the universal presence
as 115 million people are expected to have AD in the year of core attributes, specifically progressive dementia in
2050 (Dartigues, 2009). The social and economic costs the context of characteristic lesions in the brain: senile
of the disease will rise accordingly (Wimo et al., 2013), (Ab) plaques and neurofibrillary (tau) tangles.

*Correspondence to: Lary C. Walker, Department of Neurology, Emory University, 505M Whitehead Building, 615 Michael Street,
Atlanta GA 30322, United States. Tel: +1 404-727-7779, E-mail: lary.walker@emory.edu
304 L.C. WALKER
Dementia can be defined as “a decline from a per- vitamin B12 deficiency, as intervention in these instances
son’s previously established level of intellectual func- might at least partially restore cognitive function
tion that is sufficient to interfere with the everyday (Tripathi and Vibha, 2009; Holtzman et al., 2011).
performance of that individual” (Holtzman et al.,
2011). Based on the criteria set forth in the fifth edition
Genetics
of the Diagnostic and Statistical Manual of Mental Dis-
orders (DSM-5: American Psychiatric Association, The probability of developing AD is influenced by
2013), dementia due to AD is defined as “the insidious certain genetic risk factors, which include rare caus-
onset and gradual progression of substantial impair- ative, autosomal-dominant mutations with essen-
ment in learning and memory and at least one other cog- tially complete penetrance, as well as diverse genetic
nitive domain (complex attention, executive function, polymorphisms that modulate risk to varying degrees
language, perceptual-motor, or social cognition) that (Tanzi, 2012; Wingo et al., 2012). Autosomal-dominant
interferes with independence in everyday activities” mutations associated with AD all occur in the genes that
(Walker and Jucker, 2017). An important feature of code for the Ab precursor protein (APP) or for
these definitions is that the impairments are substantial, presenilin-1 or presenilin-2 (the presenilins being key
and thus become incapacitating even under ordinary components of intramembranous protease complexes
circumstances. that liberate Ab from APP (Hardy, 2006; Holtzman
et al., 2011)). The gene encoding APP is on chromosome
21, and the genes encoding presenilin-1 and presenilin-2
Differential diagnosis and biomarkers
are on chromosomes 14 and 1, respectively.
Until recently, senile plaques and neurofibrillary tan- AD-linked mutations in the presenilins and in the APP
gles could only be identified by microscopic analysis regions flanking Ab alter the processing of APP, but
of brain samples, but increasingly sensitive and specific mutations within the Ab segment of APP often modify
diagnostic tests are emerging that enable the detection its potential to aggregate and its tissue-specificity
of proteopathic abnormalities in living subjects. These (Holtzman et al., 2011; Haass et al., 2012). An unusual
include radiolabeled imaging agents for Ab and tau in variant in the APP gene that results in an alanine to thre-
the brain, and assays for quantitation of the proteins onine substitution at position 2 of Ab reduces the produc-
in cerebrospinal fluid (CSF) (Lewczuk et al., 2015; tion (Jonsson et al., 2012) and aggregation proclivity
Olsson et al., 2016; Villemagne et al., 2017). Investiga- (Benilova et al., 2014) of Ab, thereby lowering the risk
tions of these biomarkers indicate that the disease of AD (Jonsson et al., 2012). In contrast, an alanine to
process begins two decades or more before the onset valine replacement at this position increases the produc-
of demonstrable cognitive impairment (Jack et al., tion and aggregability of Ab, causing an autosomal-
2010; Jack and Holtzman, 2013). In addition, the pres- recessive type of AD (Di Fede et al., 2009) with unusual
ence of genetic risk factors such as the e4 allele of neuropathologic features (Giaccone et al., 2010). Fur-
apolipoprotein E (APOEe4) can reinforce the in-life thermore, because most patients with Down syndrome
diagnosis of AD. (trisomy 21) have an extra copy of the APP gene on chro-
It is important to place AD in the context of other brain mosome 21, they are at greatly increased risk of develop-
changes that impair intellectual capacities in the elderly. ing AD as they age (Head et al., 2016). Together, these
In younger patients with autosomal-dominant causes of genetic data consistently implicate Ab in the ontogeny
AD (below), the disease is relatively unambiguous of heredofamilial forms of AD.
histopathologically, i.e., lesions other than plaques and Dominant and recessive genetic causes account for
tangles are rare. With advancing age, additional disorders less than 1% of all AD cases (Holtzman et al., 2011).
are increasingly likely to contribute to dementia, includ- How, then, are genetics linked to idiopathic AD?
ing cerebrovascular disease, hippocampal sclerosis, and A study of twins in Sweden indicated that the heritability
cerebral proteopathies such as a-synucleinopathy, TDP- for AD is as high as 79% (Gatz et al., 2006), although
43 proteopathy, and others (Vonsattel and Hedley-White, most of the implicated polymorphisms individually have
2001; Nelson et al., 2012). These maladies can cause only a slight influence on risk (Humphries and Kohli,
dementia on their own, but they also sometimes coexist 2014). An exception is the gene that encodes apolipopro-
with AD, complicating diagnosis, exacerbating the clin- tein E (ApoE) (Yu et al., 2014), a protein that mediates
ical course, and likely diminishing the effectiveness of lipid transport throughout the body and is the major apo-
treatments directed at only one of the conditions. In addi- lipoprotein in the brain (Chouraki and Seshadri, 2014).
tion, potentially reversible causes of a dementia-like state The three major protein isoforms of ApoE in human
must be ruled out, such as depression, infections, drugs populations are ApoE2, ApoE3, and ApoE4. The most
and drug interactions, thyroid dysfunction, tumors, and frequent isoform is ApoE3 (
78%), followed by ApoE4
 PRION-LIKE MECHANISMS IN ALZHEIMER DISEASE 305
(
14%) and ApoE2 (
8%) (Liu et al., 2013). Bearers
of the APOEe4 allele have an allele dose-dependent
increase in the risk of AD, with heterozygotes having
a two- to fivefold increase in risk, and homozygotes a
12–15-fold increase (Chouraki and Seshadri, 2014). The
mechanism by which APOEe4 predisposes carriers to
AD is probably multifaceted (Potter and Wisniewski,
2012; Yu et al., 2014; Huang et al., 2017), but it is known
that bearers of APOEe4 begin to accumulate Ab in the
brain at least a decade earlier in life than do nonbearers
(Warzok et al., 1998; Walker et al., 2000; Resnick et al.,
2015). Thus, APOEe4, like the known dominant and
recessive genetic risk factors (above), appears to augment
the probability of developing AD by advancing the onset
of the Ab cascade. Indeed, all known AD-linked muta-
tions affect the production, removal, trafficking, or ten-
dency to aggregate of Ab (Hardy and Selkoe, 2002).

Other risk factors

Fig. 16.1. The canonic neuropathologic features of Alzheimer
In addition to the genetic risk factors for AD, numerous disease include senile (Ab) plaques (reddish brown) and neu-
environmental and endogenous risk factors have been rofibrillary (tau) tangles (black). Ab was immunostained with
identified. These include advancing age, traumatic brain rabbit polyclonal antibody R398 to Ab42, and tau was immu-
injury, diabetes and metabolic disorders, inflammation, nostained with mouse monoclonal antibody MC1 to paired
vascular disorders, gender, and lifestyle (Holtzman helical filaments. CA1 field of the hippocampus. Bar ¼ 50 mm.
et al., 2011; Killin et al., 2016; Lafortune et al., 2016;
Pike, 2017). In some instances these should be consid-
ered as risk factors for dementia, broadly defined, rather nm-diameter fibrils with a characteristic cross-b X-ray
than for AD per se. For example, multiple small infarcts diffraction pattern and cross-polarization-induced bire-
might raise the likelihood of dementia independently of fringence after staining with the dye Congo red (Sipe
AD, or they may advance the onset of dementia in people et al., 2016), indicative of increased b-sheet molecular
who also are incubating AD pathology in the brain. structure (Eisenberg and Jucker, 2012). In some biologic
circumstances the amyloid state is functionally advan-
THE NEUROPATHOLOGY OF AD IN THE tageous, particularly in prokaryotes (Fowler et al.,
CONTEXT OF THE PRION PARADIGM 2007; Greenwald and Riek, 2010) (amyloid-like fibrils
consisting of stacked, cross-a helices have been identi-
Amyloid
fied in the bacterium Staphylococcus aureus (Tayeb-
As in the case of most proteopathies, the proteins that are Fligelman et al., 2017), but a-helix-based amyloid has
implicated in the development of AD are structurally not been described in eukaryotes). In mammals, amyloid
abnormal manifestations of proteins that are normally is often pathogenic; more than 30 different amyloidoses
generated by cells. The abnormalities often involve an have been reported (Sipe et al., 2016), many of which
altered three-dimensional architecture (misfolding), occur outside the central nervous system (Westermark
which can be promoted by amino acid substitutions, et al., 2017).
posttranslational modifications, sequence expansions Within the brain, it is not uncommon to find some
or truncations, and such characteristics of the local milieu degree of Ab amyloidosis and tauopathy in the elderly;
as temperature and pH (Eisenberg and Jucker, 2012). In in those with dementia, abundant Ab plaques and tau tan-
addition, factors that increase the concentration of certain gles are the two types of amyloid that are pathognomonic
proteins (e.g., by raising their production or impairing for AD (Holtzman et al., 2011; Nelson et al., 2012)
their removal/degradation) can elevate the risk of disease (Fig. 16.1). The formation of amyloid by Ab and tau is
(Jucker and Walker, 2013). an obvious sign of a proteopathic process, but small olig-
A frequent indication that a protein is structurally cor- omeric assemblies may actually be the more toxic form
rupted at the molecular level is its enhanced tendency to of the proteins (Lambert et al., 1998; Haass and Selkoe,
form amyloid. In general, amyloid is a state in which a 2007; Gerson and Kayed, 2016; Yang, 2017). Ab in the
protein accumulates in tissues as masses of
10- amyloid state is virtually always present in AD, but an
306 L.C. WALKER
instructive exception is a rare hereditary type of AD Crary et al., 2014; Kovacs, 2015); in many conditions
caused by a mutation that changes glutamate to glycine however, tauopathy is secondary to various types of injury
at position 22 of Ab (E22G; the “arctic” mutation). This or stress to the brain (Nelson et al., 2012). In human prion
mutation results in early-onset AD in which Ab plaques diseases, tauopathy is variable in appearance and degree
lack the prototypical amyloid cores (Kalimo et al., 2013), (DeArmond et al., 2004; Kovacs et al., 2017), and in
indicating that “amyloid” in the strict sense is not instances where it is relatively prominent (such as
required to drive the Ab cascade. Similarly, even though Gerstmann–Str€aussler–Scheinker disease and variant
misfolded prion protein (PrP) has an enhanced ability Creutzfeldt–Jakob disease (CJD)) the cytology and ana-
to form amyloid, PrP amyloid per se is not obligatory tomic distribution often differ from those seen in AD
for the expression of prion disease (DeArmond and (Giaccone et al., 2008; Kovacs et al., 2017).
Prusiner, 1995).
This point bears emphasis because of the unproduc-
The extended neuropathology of AD
tive controversy (Drachman, 2014) that still bedevils
the “amyloid cascade hypothesis” (aka the “amyloid In addition to the canonic lesions that define AD – Ab
hypothesis”) of AD (Hardy and Selkoe, 2002; Selkoe plaques and tau tangles – other changes are present
and Hardy, 2016). The “amyloid” in the original formu- in the brain that complicate the disease phenotype.
lation of this concept refers to b-amyloid (i.e., Ab in a One is the accumulation of Ab in and around the walls
b-sheet-rich, polymerized state). There can be little doubt of cerebral blood vessels, a condition known as Ab-
that Ab is a driving force in the genesis of AD (Jack et al., type cerebral amyloid angiopathy (Ab-CAA). Ab-CAA
2010; Selkoe, 2011; Bateman et al., 2012; Walker and weakens the vascular wall and elevates the risk of intracra-
Jucker, 2015), or that b-amyloid accumulation per se is nial hemorrhage (Biffi and Greenberg, 2011). Like Ab
detrimental to cognition, particularly when embodied plaques and tauopathy, Ab-CAA is not specific to AD,
as neuritic plaques (Nelson et al., 2012). However, tauo- and its prevalence increases with advancing age (Revesz
pathy is an essential downstream consequence that cor- et al., 2003; Biffi and Greenberg, 2011). However, some
relates more strongly with the degree of dementia than degree of Ab-CAA is almost always present in AD
does the number of Ab plaques (Wilcock and Esiri, (Attems and Jellinger, 2014; Vinters, 2015; Kapasi and
1982; Crystal et al., 1988; Bierer et al., 1995). This appar- Schneider, 2016), and it is severe in around 25% of cases
ent inconsistency mainly reflects the importance of tauo- (Charidimou et al., 2012). The factors that drive the incon-
pathy for the clinical expression of the disease, but it does sistent occurrence of Ab-CAA in different people remain
not invalidate the instigating role of multimeric Ab in uncertain.
AD. A review of published work by the Alzheimer’s Other alterations are found to variable extents among
Disease Neuroimaging Initiative concluded that “CSF end-stage AD cases, and most of these anomalies lack
biomarkers are consistent with disease trajectories pre- diagnostic specificity for the disease. Macroscopically,
dicted by b-amyloid cascade … and tau-mediated neuro- loss of brain tissue and concomitant expansion of the
degeneration hypotheses for AD” (Weiner et al., 2013). ventricles are common, but this varies among regions
Because tau and Ab both self-aggregate by the templated and among patients (Hauw and Duyckaerts, 2001).
corruption of like proteins by misfolded seeds, once Evidence of inflammation includes reactive microglia
tauopathy is set in motion, it is possible that the two pro- and astrocytes, especially in association with Ab pla-
teopathies progress along separate paths, both temporally ques, as well as increased inflammatory mediators such
and spatially. as cytokines (Duyckaerts et al., 2009). Granulovacuolar
The tau protein normally is involved in the stabiliza- degeneration, perisomatic granules, and Hirano bodies
tion of cellular microtubules (Spillantini and Goedert, may be present (Duyckaerts et al., 2009), but their signif-
2013). In AD and other tauopathies, tau misfolds and icance for AD per se is uncertain. Many different neuronal
becomes hyperphosphorylated; like Ab, the altered tau systems are compromised in AD (Mann and Yates, 1986;
molecules aggregate to form soluble oligomers and long, Hauw and Duyckaerts, 2001), some more markedly than
b-sheet-rich polymers that have the characteristics that others, and synapses are regionally depleted (Terry et al.,
define amyloid. The tau fibrils bundle together as neuro- 1999; Duyckaerts et al., 2009). In some cases of AD,
fibrillary tangles in neurons (Fig. 16.1), although tauopa- spongiform change is evident that, though generally less
thy also can afflict glial cells (Kovacs, 2015). severe, can resemble that seen in CJD (Smith et al.,
Tauopathy occurs in association with many brain 1987; Sherzai et al., 2013) (Fig. 16.2). As noted above,
disorders besides AD (Nelson et al., 2012). The primary other neurodegenerative conditions might be present in
tauopathies are disorders in which tau aggregation is the brain along with the lesions of AD, particularly in older
the major abnormality (Spillantini and Goedert, 2013; patients.
 PRION-LIKE MECHANISMS IN ALZHEIMER DISEASE 307

Fig. 16.2. Spongiform change (vacuoles, seen in these micrographs as white holes) in the neocortex of an Alzheimer disease
patient (A) and in a patient with Creutzfeldt–Jakob disease (B). Spongiform change is not unique to prion diseases, but it is less
common in Alzheimer disease, and when it occurs it is generally mild (Smith et al., 1987; Sherzai et al., 2013). Hematoxylin and
eosin stain. Bar ¼ 50 mm.

Regardless of the complexity of damage to the brain, to aggregate in the living brain by a prion-like mecha-
the essential and unifying feature of AD is the obligatory nism (Kane et al., 2000). These studies showed that
presence of aggregated Ab and tau proteins. For this rea- Ab plaques and CAA are seedable by brain
son, extensive research has been directed toward deter- extracts from AD patients, but not by extracts derived
mining how the proteins misfold, self-assemble, and from control brains that were devoid of aggregated
propagate their pathogenic features, a process that shares Ab (Kane et al., 2000; Walker et al., 2002; Meyer-
important commonalities with the molecular pathogene- Luehmann et al., 2006) (Fig. 16.3). AD brain extracts
sis of prion diseases (Walker and LeVine, 2000; Walker infused into the brains of wild-type mice (which express
et al., 2006, 2016; Jucker and Walker, 2013; Prusiner, an aggregation-resistant sequence of Ab) did not yield
2013; Goedert, 2015; Walker and Jucker, 2015). Ab deposits.
Subsequent experiments showed unequivocally that
THE PRION-LIKE PROPERTIES OF the active agent is aggregated Ab, and that the ability
AGGREGATED Ab of Ab to seed as well as the characteristics of the resulting
deposits are governed by both the agent and the host
The idea that AD might arise by a pathogenic mechanism
(Meyer-Luehmann et al., 2006). These findings have
similar to that of prion diseases has a fairly long history
been confirmed and extended by other laboratories
(Farquhar and Gajdusek, 1981; Prusiner, 1984). Based
(Watts et al., 2011, 2014; Morales et al., 2012, 2015a;
on their success in transmitting kuru and CJD to nonhu-
Stohr et al., 2012, 2014; Duran-Aniotz et al., 2013, 2014;
man primates (Gajdusek et al., 1966, 1968; Gibbs
Burwinkel et al., 2018), and the collective experiments
et al., 1968), and on the hypothesis that a “slow virus”
have established that the molecular features of Ab seeds
might be involved in other neurodegenerative disorders
are essentially the same as those that define the patho-
(Gajdusek, 1977), D. Carleton Gajdusek’s group
genicity of prions (Jucker and Walker, 2013; Morales
attempted to experimentally transmit AD to several spe-
et al., 2015b; Walker and Jucker, 2015; Walker et al.,
cies of nonhuman primates via intracerebral injection of
2016). Key commonalities between Ab seeds and PrP-
AD brain homogenates. They tentatively reported that
prions are summarized as follows:
the attempt was unsuccessful (Goudsmit et al., 1980).
In Great Britain, Ridley and Baker et al. (1994) under- 1. The active seeding agent is a form of the protein
took similar transmission experiments in marmosets itself. In addition to brain extracts from AD patients,
(Callithrix jacchus). After an incubation period of more extracts from APP-transgenic mice (Meyer-
than 5 years, they detected a significant increase in the Luehmann et al., 2006) and aged monkeys (Rosen
senile plaque load of the host animals. The causative et al., 2016) can seed Ab deposition as long as aggre-
agent, however, remained uncertain. gated Ab is present in the donor brain. The degree of
When transgenic mouse models expressing human- Ab seeding is directly related to the concentration of
type APP became available, experiments were initiated Ab in the brain extract (Meyer-Luehmann et al.,
to explicitly test the hypothesis that Ab can be induced 2006; Fritschi et al., 2014b), and even extremely
308 L.C. WALKER

Fig. 16.3. Seeded Ab deposition (brown) in the hippocampus of an 8-month-old TG2576 Ab-precursor protein-transgenic mouse
(sagittal sections; rostral is to the right). The hippocampus of one hemisphere (A) was injected 5 months earlier with clarified
cortical extract from an Alzheimer disease case, and the contralateral hippocampus (B) received a similar amount of control brain
extract lacking aggregated Ab. The induced deposits emerge histologically in this model after around 2–3 months, and increase
thereafter. Sections were incubated with polyclonal antibody R398 to Ab42. Hematoxylin counterstain (blue). Bar ¼ 200 mm.

small amounts of Ab seeds are capable of stimulat- Distinct prion strains often yield characteristic pat-
ing aggregation in the brain (Fritschi et al., 2014b; terns of lesion structure and distribution in the brain
Morales et al., 2015a). Immunodepletion of Ab from (Peretz et al., 2002; DeArmond et al., 2004). An
the donor extract prior to injection nullifies the seed- important indication that variant CJD (the human
ing effect (Meyer-Luehmann et al., 2006; Duran- prionosis that is linked to bovine spongiform enceph-
Aniotz et al., 2014). Synthetic, pre-aggregated Ab alopathy) is caused by a novel prion strain was the
is capable of seeding deposition in vivo (Stohr discovery of atypical lesions termed florid plaques
et al., 2012), albeit relatively weakly (see below). in affected humans (Ironside et al., 2000).
2. Ab seeds are rich in b-sheet secondary structure. As in the case of PrP-prions, Ab can fold into strain-
Amyloid fibrils of all types, including Ab-amyloid like variants both in vitro (Petkova et al., 2005; Nilsson
and PrP-amyloid, are rich in b-sheets in which the et al., 2007; Yagi et al., 2007; Paravastu et al., 2008;
individual b-strands run approximately perpendicu- Meinhardt et al., 2009; Kodali et al., 2010; Miller
lar to the long axis of the fibrils (Eisenberg and et al., 2010; Agopian and Guo, 2012; Spirig et al., 2014;
Jucker, 2012). In vitro studies by Lansbury and Tycko, 2015, 2016) and in vivo (Meyer-Luehmann
colleagues demonstrated that pre-aggregated, b- et al., 2006; Rosen et al., 2010, 2011; Heilbronner
sheet-rich seeds of synthetic Ab efficiently induce et al., 2013; Lu et al., 2013; Stohr et al., 2014;
monomeric Ab to acquire b-sheet and assemble into Watts et al., 2014; Cohen et al., 2015; Condello
amyloid (Harper and Lansbury, 1997). In addition, et al., 2018; Rasmussen et al., 2017). Cerebral Ab
in vivo seeding experiments have shown that assemblies in humans with AD vary in terms of
denaturation of Ab-seed-rich brain extracts with plaque morphology (Wisniewski et al., 1989; Thal
formic acid (which disrupts the three-dimensional et al., 2006), ligand-binding characteristics (Rosen
architecture of proteins) negates the ability of the et al., 2010; Condello et al., 2018; Rasmussen et al.,
extracts to induce plaque formation (Meyer- 2017), solid-state nuclear magnetic resonance features
Luehmann et al., 2006). (Qiang et al., 2017), as well as conformational stability
3. Misfolded Ab can manifest as structurally and func- and other biophysical characteristics (Cohen et al.,
tionally variant strains. In the canonic (PrP) prion 2015). Interestingly, Ab extracted from the autopsied
diseases, prion traits and the host response vary in brains of nondemented elderly subjects exhibits
ways that suggest alternative structural and func- molecular-level features that differ in some ways from
tional “strains” of the agent. Strain differences, in AD-derived Ab (Piccini et al., 2005; Portelius et al.,
turn, have been linked to dissimilarities in PrP amino 2015). Whether these differences are indicative of
acid sequence, protease sensitivity, resistance to dena- fundamentally distinctive strains of Ab, or whether
turants, and glycosylation patterns (McKintosh et al., they reflect early versus late stages in the pathogenesis
2003; Weissmann, 2004; Wiseman et al., 2015). of AD, is not certain.
However, a critical factor governing prion infectivity Experimental studies in transgenic mice have
and disease phenotype is the molecular conformation shown that strain-like features of aggregated Ab can
of pathogenic PrP (PrPTSE or PrPSc) (Peretz et al., be transferred from donor to host by exogenous seed-
2002; Tanaka et al., 2006; Gambetti et al., 2011). ing. Specifically, in the absence of seeding, APP23
 PRION-LIKE MECHANISMS IN ALZHEIMER DISEASE 309
mice and APP/PS1 mice develop Ab plaques with dif- interconnected regions (Hamaguchi et al., 2012;
ferent morphologies and ratios of the 40- and Ye et al., 2015b). In APP-transgenic mouse models,
42-amino acid lengths of Ab (Ab40 and Ab42); when Ab seeds injected into the peritoneal cavity (Eisele
Ab seeds from one transgenic mouse model were et al., 2010, 2014) or intravenously (Burwinkel
infused intracerebrally into the other, the plaque mor- et al., 2018) travel to the brain, where many of the
phology (Meyer-Luehmann et al., 2006), spectral sig- induced deposits are associated with cerebral blood
nature of bound conformation-sensitive thiophene vessels.
ligands, and the Ab40:42 ratio (Heilbronner et al., The cellular mechanisms involved in the traffick-
2013) were influenced both by the source of the seeds ing of Ab seeds remain uncertain. Extracellular,
and the type of murine host. In addition, strain-like fea- soluble Ab is taken up by cultured cells and
tures of Ab from human AD cases can be at least par- concentrated in the acidic environment of endo-
tially replicated in mouse models (Rasmussen et al., somes/lysosomes, where the Ab assembles into
2017; Condello et al., 2018). higher-molecular-weight seeds (Hu et al., 2009).
4. Ab seeds vary in size and sensitivity to proteinase K. Oligomeric Ab seeds have been described that are
Infectious PrP prions exist in a wide range of sizes, bound to intracellular membranes and that strongly
the most potent of which are small and soluble stimulate Ab aggregation in vitro and in vivo
(Silveira et al., 2005). Similarly, Ab seeds can range (Marzesco et al., 2016). In cell culture experiments,
from large fibrils to small, oligomeric seeds with Ab seeds were demonstrated to spread by transfer
high biologic potency (Langer et al., 2011). Large from neuron to neuron (Nath et al., 2012; Domert
Ab seeds are relatively resistant to inactivation by et al., 2014), and neuroanatomic patterns of deposi-
proteinase K, whereas – like PrP prions – oligomeric tion are consistent with spread along neuronal
Ab seeds are readily inactivated by the enzyme pathways (Hamaguchi et al., 2012; Ronnback
(Langer et al., 2011). et al., 2012; Ye et al., 2015b) by active cellular trans-
5. Some Ab seeds are durable. When Ab-rich brain port and/or diffusion (Eisele and Duyckaerts, 2016).
extracts are boiled for 5 minutes prior to infusion In addition, there is evidence that macrophages can
into host mice, a significant fraction of bioactive phagocytose and translocate Ab seeds (Eisele et al.,
Ab seeds remain (Meyer-Luehmann et al., 2006). 2014; Cintron et al., 2015).
In addition, similar to PrP prions, Ab seeds retain Small, cell-derived extracellular vesicles such as
their potency in donor brain tissue that has been in exosomes have been linked to the transmissibility
formaldehyde for years (Fritschi et al., 2014a). Ab of PrP-prions (Fevrier et al., 2004; Properzi et al.,
seeds also are durable within the living brain; they 2015; Guo et al., 2016a). Extracellular vesicles
retain some bioactivity (albeit with progressively also have been suggested to ferry Ab between
diminishing potency) for at least 6 months after infu- cells (Rajendran et al., 2006), although their
sion into the brains of mice engineered to lack APP, influence on the pathogenesis of AD – positive or
and which therefore are incapable of replicating Ab negative – remains uncertain (Joshi et al., 2015).
in any form (Ye et al., 2015a). Analogously, PrP 7. Ab aggregation can be instigated de novo. PrP
prions have been reported to persist in the brains prions induce prion disease in animals that are
of PrP-deficient mice for up to 600 days (Diack unlikely to have acquired the disease without expo-
et al., 2016). Likewise, AA amyloidosis in systemic sure to exogenous prions. In contrast, many of the
organs can be promoted by fibrillar AA seeds (amy- experiments showing seeding of Ab have been
loid-enhancing factor) that persist in mice for at least undertaken in transgenic mouse models that, with
6 months (Lundmark et al., 2002). The endurance of age, eventually develop Ab plaques and CAA spon-
some proteopathic seeds may result from their abil- taneously. To determine whether Ab deposition can
ity to adopt the highly stable, b-sheet-rich amyloid be seeded in normally resistant animals, Ab-seed-rich
state (see above). brain extracts were injected intracerebrally into trans-
6. Ab seeds spread systematically within the brain. As genic rodent models that do not generate Ab lesions
with PrP prions (Fraser, 1982; Buyukmihci et al., within their average lifespans; these studies indicate
1983; Kimberlin and Walker, 1986; Liberski et al., that Ab deposition is inducible de novo, and in this
2012; Rangel et al., 2014) and other proteopathic paradigm is not simply an acceleration of an ongoing
seeds (Clavaguera et al., 2009, 2013; Ahmed process (Morales et al., 2012; Rosen et al., 2012).
et al., 2014; Iba et al., 2015; Boluda et al., 2015; 8. Ab proteopathy is serially transmissible. Similar to
Hock and Polymenidou, 2016; Rey et al., 2016), PrP-prions, different strains of Ab seeds can be
Ab seeds introduced into one part of the brain induce successively transmitted from the initially seeded
protein aggregation that spreads systematically to mice to subsequent hosts (Watts et al., 2014).
310 L.C. WALKER
PRION-LIKE PROPERTIES OF Ab: OPEN Rushworth et al., 2013; Hu et al., 2014; Lauren, 2014)
QUESTIONS or beneficial (when it occurs in extracellular vesicles
(Falker et al., 2016) or between Ab and soluble (glyco-
Pure, pre-aggregated synthetic Ab is able to seed depo-
phosphatidylinositol anchor-free) PrP (Nieznanski
sition in vivo, but synthetic Ab seeds are much weaker
et al., 2012)).
than are Ab seeds derived from the brain (Stohr et al.,
2012). Correspondingly, generating infectious prions
from purified, recombinant PrP has long been a challenge
THE PRION-LIKE PROPERTIES OF
(Legname et al., 2004). Both Ab seeds and PrP prions
AGGREGATED TAU
thus are most potent when they are generated within liv- At the ultrastructural level, neurofibrillary tangles in AD
ing tissues. The infectivity of recombinant PrP-prions consist predominantly of characteristic paired helical fil-
can be augmented by adding certain cofactors to the aments (Crowther, 1991) that result from the ectopic
medium during aggregation (Wang et al., 2010; polymerization of hyperphosphorylated tau protein
Deleault et al., 2012; Zhang et al., 2014). It is possible (Lee et al., 2001; Spillantini and Goedert, 2013). Tau
that specific cofactors also are required to optimize the hyperphosphorylation is thought to be an early stage in
bioactivity of Ab seeds in vivo. The lipid environment, the formation of tangles (although it can occur as a
for instance, influences the pathobiology of Ab reversible phenomenon under such conditions as fetal
(Morgado and Garvey, 2015), and lipids are essential development, hibernation, and hypothermia: Spillantini
for the high-affinity binding of the b-amyloid imaging and Goedert, 2013).
agent Pittsburgh compound B to cerebral Ab (Matveev Considerable evidence now supports the inclusion of
et al., 2014). Potent, in vivo active Ab seeds recently tauopathy among the disorders that share a prion-like
have been generated by the seeded conversion of syn- mechanism of pathogenesis. Similar to in vivo Ab seed-
thetic Ab in a hippocampal slice culture model ing, the accumulation of hyperphosphorylated tau is
(Novotny et al., 2016). Clarifying the conditions that inducible in the brains of tau-transgenic host mice by infu-
influence protein aggregation, seeding, and toxicity in sion of aggregated tau seeds (Clavaguera et al., 2009,
living systems could disclose new therapeutic objectives 2015; Guo and Lee, 2011; Holmes et al., 2014; Peeraer
for multiple proteopathies. Insights might also emerge et al., 2015; Polanco et al., 2016; Gerson et al., 2016;
from an analysis of senescent nonhuman primates which, Takeda et al., 2016). The ensuing tauopathy spreads sys-
despite substantial accumulation of human sequence Ab tematically from the site of injection to axonally connected
with age, exhibit neither significant tauopathy nor regions of the brain (Clavaguera et al., 2009, 2013; Ahmed
dementia (Rosen et al., 2016). A possible parallel in et al., 2014; Stancu et al., 2015; Narasimhan et al., 2017),
the prion field is the dissociation of PrP amyloid seeding consistent with the uptake, transport, and discharge of tau
and transmission of spongiform encephalopathy in a seeds by neurons (Frost et al., 2009; Wu et al., 2013;
mouse model (Piccardo et al., 2013). Sanders et al., 2014). Neuronal activity augments the
Another open question is why the Ab that is present in release of tau from cells in vitro, and also increases the
the CSF of AD patients only weakly seeds the aggrega- amount of tauopathy in vivo (Wu et al., 2016). Addition-
tion of synthetic Ab in vitro, and fails to seed deposition ally, tau antisense oligonucleotides decrease tau expres-
in the brains of APP-transgenic mice, even at Ab concen- sion and pathology in mouse models, and also reverse
trations that exceed the levels in brain extracts by a factor pathologic tau seeding (DeVos et al., 2017). Like Ab pro-
of 10 (Fritschi et al., 2014b). The reasons for the poor teopathy and prion disease, tauopathy can be induced in
seeding efficiency of CSF Ab are unknown, but the the brain by tau seeds that have been infused into the peri-
Ab assemblies in CSF were found to be smaller and toneal cavity (Clavaguera et al., 2014), and bioactive tau
mostly devoid of N-terminally truncated variants com- seeds exist in a range of sizes (Lasagna-Reeves et al.,
pared to brain-derived Ab (Fritschi et al., 2014b). Addi- 2012; Mirbaha et al., 2015; Gerson et al., 2016; Jackson
tionally, other substances in the CSF, such as cystatin et al., 2016).
C (Kaeser et al., 2007), might interfere with the seeding Brain extracts from donors with clinicopathologically
capacity of multimeric Ab. distinct human tauopathies induce tau lesions in host
Finally, in an intriguing intersection of disease-related mice that resemble the lesions in the corresponding
proteins, the normal, cellular form of the prion protein human disorders (Clavaguera et al., 2013; Sanders
(PrPC) was discovered to be a cell surface receptor for et al., 2014; Boluda et al., 2015; Narasimhan et al.,
oligomeric Ab (Salazar and Strittmatter, 2016). The 2017), indicating that tau, like Ab and PrP, can misfold
implications of the Ab–PrP interaction for AD appear into replicable proteopathic strains (Sanders et al.,
to be complex, as its impact on Ab toxicity or aggrega- 2014). At the cellular level, multimeric tau is taken up
tion may be either deleterious (Um et al., 2012; by a heparan sulfate proteoglycan-associated mechanism
 PRION-LIKE MECHANISMS IN ALZHEIMER DISEASE 311
(Holmes et al., 2013), and the aggregates enter cells via transgene is weakly expressed in other brain regions,
macropinocytosis (Holmes et al., 2013; Falcon et al., which could influence the pattern of lesion progression
2015). Tau strains instigate distinct regional and cellular (Yetman et al., 2016). However, when considered in light
patterns of inclusions, and the strains can be reliably of the orderly neuroanatomic localization of tau lesions in
propagated in cell cultures (Kaufman et al., 2016). The interconnected brain regions in AD (Saper et al., 1987;
bioactivity of tau strains in HEK cells was shown to be Arnold et al., 1991; Braak and Braak, 1995), the experi-
governed by the isoform composition (3-repeat and/or ments in mouse models implicate neuronal transport and
4-repeat) of the tau seeds along with the isoform expres- cytotic mechanisms in the propagation of tau seeds within
sion by the host cells (Woerman et al., 2016). Tau seeds the nervous system. This possibility is indirectly supported
are present in the human brain early in the development by evidence for the neuronal trafficking of Ab seeds, PrP
of tauopathy, and possibly prior to the histologic appear- prions, and other proteopathic seeds, as described above.
ance of hyperphosphorylated tau within neurons Furthermore, in vivo imaging studies of the regional accu-
(Furman et al., 2017). mulation of pathogenic proteins in relation to the connect-
Tau seeding differs from Ab seeding in that tauopathy edness of the affected areas implicate the connectome
is readily inducible by AD brain extracts in nontrans- in the systematic spread of seeds in AD and other neuro-
genic (wild-type) mice (Audouard et al., 2016; Guo degenerative disorders (Bero et al., 2011; Zhou et al., 2012;
et al., 2016b). In addition, recombinant tau fibrils can Iturria-Medina et al., 2014; Raj et al., 2015).
fairly efficiently instigate tauopathy in tau-transgenic
mice (Lasagna-Reeves et al., 2012; Clavaguera et al.,
PRION-LIKE SEEDING AND AD
2013; Iba et al., 2013; Peeraer et al., 2015), although
PATHOLOGY IN HUMANS
the potency of recombinant tau is less than that of tau that
originates in brain samples (Falcon et al., 2015). Recom- Between 1958 and 1985, approximately 30,000 children
binant tau fibrils did not seed tauopathy in wild-type received a series of injections of cadaver-derived human
mice, possibly due to distinct conformational differences growth hormone (c-hGH), in most instances to correct a
between artificially assembled fibrils and those gener- deficiency in growth (Will, 2003; Brown et al., 2012). To
ated in the brain (Guo et al., 2016b). obtain sufficient hormone for treatment, human pituitary
In the CSF of AD patients and transgenic mice expres- glands were collected at autopsy, pooled into large
sing human-type tau, seed-competent tau is present that batches, homogenized, and the c-hGH chemically
can stimulate tauopathy in cultured cells (Takeda et al., extracted for injection. The treatment successfully stim-
2016), and some tau seeds in AD CSF appear to be asso- ulated growth, but years after treatment had ceased, a
ciated with extracellular vesicles (Wang et al., 2017). The small percentage of the c-hGH recipients developed
seeding capability of CSF tau in vivo, however, has not CJD (Brown et al., 2012). Subsequent studies have con-
been reported; because CSFAb does not readily seed pla- firmed that the growth hormone was contaminated with
ques or CAA in APP-transgenic mice (Fritschi et al., PrP prions, which presumably originated from pituitaries
2014b) (see above), a similar analysis of in vivo tau seed- inadvertently obtained from patients who had died with
ing by CSF from patients with AD (and other tauopa- prion disease (Jucker and Walker, 2015). In 1985,
thies) in the appropriate models could be informative. cadaver-derived hGH was replaced by recombinant
These experiments collectively underscore the prion- growth hormone, thereby effectively eliminating the pos-
like molecular properties of aggregated tau, but current sibility that the therapeutic agent would be contaminated
evidence indicates that tauopathy, like Ab-proteopathy, by prions (Brown et al., 2012).
is not infectious in the customary sense of being facilely Hypothesizing that pituitaries collected from AD
transmissible from one organism to another (Walker and patients were likely to be included in the batches for hor-
Jucker, 2015). Rather, in AD, the process of tau misfold- mone extraction, Jaunmuktane et al. (2015) sought evi-
ing and propagation takes place entirely within the dence of AD-like pathology in 8 c-hGH recipients who
affected organism. To model the endogenous emergence had died of prion disease approximately 30 years after
and spread of tauopathy, genetically modified mice were treatment. The cases ranged from 36 to 51 years of age
studied in which the expression of a disease-associated at death – well before the lesions of idiopathic AD usu-
human tau transgene is restricted principally to projection ally are evident – and they lacked the major genetic risk
neurons of the entorhinal cortex (de Calignon et al., 2012; factors that would have predisposed them to early-onset
Liu et al., 2012). The mice developed tauopathy initially AD. Along with the neurodegenerative changes typical
in the entorhinal cortex, as expected, but with passing of CJD, 4 of the subjects had extensive Ab deposition
time the abnormalities successively emerged in axonally in the brain in the form of both Ab plaques and CAA,
connected brain areas (de Calignon et al., 2012; Liu and 2 others had sparse Ab deposits. Such Alzheimer-
et al., 2012). Subsequent studies have found that the tau like Ab-pathology was not present in control patients
312 L.C. WALKER

Fig. 16.4. Immunoreactive deposits (brown) of aggregated Ab (A) and hyperphosphorylated tau (B) in the posterior lobe of
the pituitary gland from a patient who had died with Alzheimer disease. Ab was detected with antibody 82E1 to the
N-terminal segment of Ab, and tau was detected with antibody CP13 to an epitope around phosphoserine 202. The accumulation
of Ab and tau is generally mild in the pituitary. Hematoxylin counterstain (blue). Bars ¼ 100 mm in (A) and 50 mm in (B).

of similar age who had died of other (non-c-hGH-related) Whether the Ab-positive recipients of c-hGH or dura
prion diseases. In addition, the frequent presence of transplants would have manifested the full AD pheno-
Ab-CAA is reminiscent of the increased vascular Ab type had they lived longer cannot be known. An analysis
deposition seen in APP-transgenic mice following of pituitary hormone recipients in the United States sug-
peripheral administration of Ab seeds (Eisele et al., gests that they are not more likely to develop AD than
2010, 2014; Burwinkel et al., 2018). those in the general population (Irwin et al., 2013). How-
Significant Ab deposition also has been reported in ever, longer-term follow-up and investigation of c-hGH
the brains of patients who died of CJD years after receiv- recipients in other countries, particularly where the pro-
ing PrP prion-contaminated dura mater transplants cessing of the hormone differed from that in the United
(Frontzek et al., 2016; Hamaguchi et al., 2016) or in States (Brown et al., 2012), will be necessary to fully
c-hGH recipients who died of causes other than CJD gauge the transmission risk of nonprion proteopathies
(Ritchie et al., 2017). The most parsimonious explana- in these instances.
tion for the presence of Ab proteopathy in the recipients
of human-derived biologics is that some batches of
growth hormone and dura mater were contaminated with CONCLUSIONS
Ab seeds in tissues originating from AD (or incipient The seeded propagation of misfolded Ab is an early and
AD) donors. This possibility is supported by evidence obligatory occurrence in the cascade of events leading to
that some pituitary glands from AD patients (Irwin the dementia of AD, but tauopathy is a critical down-
et al., 2013) (Fig. 16.4A) and also samples from impli- stream consequence that strongly impairs brain
cated c-hGH (Duyckaerts et al., 2018) and dura mater function. Both proteins have been shown to misfold,
(Kovacs et al., 2016) contain Ab. self-assemble, and convey their abnormal properties to
In light of experimental work on Ab seeding in vivo like proteins by a prion-like molecular mechanism.
(above), it is likely that a prion-like seeding mechanism Therapeutic strategies for AD stemming from the prion
underlies the development of Ab plaques and Ab-CAA paradigm include impeding the production or multimer-
in recipients of c-hGH and dura mater transplants. Surpris- ization of the proteins, uncoupling the pathogenic link
ingly, few of these iatrogenic CJD patients also had evi- between abnormal Ab and tau, and promoting the elim-
dence of significant tauopathy (Jaunmuktane et al., ination of the seeds from the brain. Because Ab proteo-
2015; Kovacs et al., 2016; Duyckaerts et al., 2018). Mild pathy and tauopathy each propagate by a prion-like
tauopathy is present in AD-derived pituitaries (Hashizume mechanism of homologous protein corruption, it is likely
et al., 2011; Irwin et al., 2013) (Fig. 16.4B), and, as dis- that, once set in motion, the two pathologic processes
cussed above, tauopathy is directly seedable by aggre- advance more or less independently. If so, targeting
gated tau in experimental models. Some c-hGH samples Ab should suffice for early prevention, but late-stage
have been found to contain tau (Duyckaerts et al., therapeutics will need to impede both branches of the
2018). Furthermore, experimental studies show that tau cascade to be optimally effective. Another practical
polymerization can be cross-seeded by aggregated Ab implication of the prion-like properties of misfolded
(Vasconcelos et al., 2016) and that tauopathy is augmented Ab and tau is to reinforce the importance of pristine
by Ab plaques in vivo (Pooler et al., 2015; Li et al., 2016). instruments in neurosurgery. Finally, recognition of the
 PRION-LIKE MECHANISMS IN ALZHEIMER DISEASE 313
prevalence of prionic mechanisms in neurodegenerative Boluda S, Iba M, Zhang B et al. (2015). Differential induction
diseases could serve to integrate research efforts on these and spread of tau pathology in young PS19 tau transgenic
intractable disorders conceptually, experimentally, and mice following intracerebral injections of pathological tau
therapeutically. from Alzheimer’s disease or corticobasal degeneration
brains. Acta Neuropathol 129: 221–237.
Braak H, Braak E (1995). Staging of Alzheimer’s disease-
ACKNOWLEDGMENTS related neurofibrillary changes. Neurobiol Aging 16:
I gratefully acknowledge insightful discussions with 271–278; discussion 278–284.
Brown P, Brandel JP, Sato T et al. (2012). Iatrogenic Creutzfeldt-
Mathias Jucker and the members of his laboratory in
Jakob disease, final assessment. Emerg Infect Dis 18:
Tuebingen, and with David Lynn, Yury Chernoff, Anil 901–907.
Mehta, and Harry LeVine. This work was supported in Burwinkel M, Lutzenberger M, Heppner FL et al. (2018).
part by National Institutes of Health grants P50 Intravenous injection of beta-amyloid seeds promotes cere-
AG025688, RR00165, and OD11132, and the Alexander bral amyloid angiopathy (CAA). Acta Neuropathol
von Humboldt Foundation. Commun 6 (1): 23. https://doi.org/10.1186/s40478-018-
0511-7. PMID: 29506560.
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