Papers by Kumar Sambamurti
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013
A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile ... more A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of β-amyloid peptide (Aβ) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Aβ levels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N 1-norPosiphen (15), (+)-N 8-norPosiphen (17) and (+)-N 1 , N 8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and and its enantiomer, the AD drug candidate (−)-phenserine (2), was assessed against APP, α-synuclein and classical
Neurobiology of Aging, 2004
Herein we review the role of apolipoprotein E (ApoE) in Alzheimer&amp... more Herein we review the role of apolipoprotein E (ApoE) in Alzheimer's disease (AD) and how ApoE interacts with various risk factors. ApoE is localized with the major pathological hallmarks of AD, extracellular amyloid deposits and intracellular neurofibrillary tangles. The ApoE4 allele is associated with the development of late-onset familial and sporadic AD. ApoE4 has a gene dose effect on the risk and age of onset of AD. ApoE mRNA and protein are found predominantly in astrocytes within the CNS. There is also a high expression of ApoE mRNA in the brains of people with sporadic AD. ApoE acts as a cholesterol transporter in the brain. Cholesterol controls amyloid production and deposition by regulating beta-secretase. In transgenic animal studies, ApoE4 expression causes neuropathology and behavioral deficits. We also discuss data from three different cohorts for AD in the general population, in different racial and ethnic groups and the role of the 4 allele in the clinical onset of the disease. Although the 4 allele is an important genetic risk factor for AD, it accounts for a fairly small fraction of disease in the population. The effect of the 4 allele on annual decline in episodic memory is significantly stronger than its effect on decline in other cognitive systems. Notably, the 2 allele has an equal and opposite effect. Thus, ApoE allele status influences risk of AD by a relatively selective effect on episodic memory. Mechanistically, the role of APoE in AD needs to be established in terms of its gene expression, which ultimately controls levels of various ApoE isoforms. Transcriptional regulation suggests complex regulation of this gene and the resultant ApoE protein in injured neurons. We discuss the characteristics of ApoE regulatory elements, including their interactions with different transcription factors, to understand ApoE gene expression. Thus, ApoE4 contributes to the pathogenesis of AD, but additional environmental risk factors will also be identified independent of ApoE and other genetic polymorphisms.
Current Alzheimer Research, 2007
ABSTRACT
Current Drug Targets, 2003
Alzheimer&amp... more Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the beta-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as beta-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and gamma-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.
Drug Development Research, 2002
Alzheimer's disease (AD), the most common form of dementia among the elderly, is a progressive, d... more Alzheimer's disease (AD), the most common form of dementia among the elderly, is a progressive, degenerative disorder of the brain with a loss of memory and cognition. A defining characteristic of AD is the deposition of amyloid fibrils and neurofibrillary tangles in the brain of afflicted individuals. Biochemically, they are mainly composed of β-amyloid protein (Aβ) and phosphorylated tau proteins, respectively. There is also a loss of the presynaptic markers of the cholinergic system, such as acetylcholine, in the brain areas related to memory and learning. The biochemical pathways leading to AD are presently unknown and are a subject of intensive study with current theories favoring a hypothesis where Aβ aggregates to toxic forms that induce tau phosphorylation and aggregation. It is believed that this ultimately leads to dysfunction and death of cholinergic neurons, and compensation for this loss had been the primary focus of first generation therapeutic agents. The amyloid and tau hypotheses have lead to a focus on amyloid and tau as therapeutic targets. The current therapeutic goals are to reduce amyloid levels, prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. AD has a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in several genes, such as the β-amyloid precursor protein (APP) and presenilins (PS1, PS2). Other genes, such as apolipoprotein E (APOE), are considered to be risk factors for AD. Several proteins, such as APP, APOE, BACE (β-amyloid cleaving enzyme), PS1/2, secretases, and tau play important roles in the pathology of AD. Therefore, attempts are being made to develop new inhibitors for BACE, PS-1 and γ-secretase for treatment of AD. There is also a significant advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE inhibitors in AD. The mechanism of a new generation of acetyl- and butyrylChE inhibitors is being studied and tested in human clinical trials for AD. Other strategies, such as vaccination, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy, are also being studied for treating or slowing the progression of AD. Developments of early diagnostic tools based on quantitative biochemical markers will be useful to better follow the course of the disease and to evaluate different therapeutic strategies. In the present review, we attempt to critically examine recent trends in AD research from neurochemical to clinical areas. We analyze various neurobiological mechanisms that provide the basis of new targets for AD drug development. These current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain to effectively diagnose and prevent their occurrence. Drug Dev. Res. 56:267–281, 2002. © 2002 Wiley-Liss, Inc.
Current Alzheimer Research, 2005
Existing cholinesterase (ChE) inhibitor therapies for Alzheimer's disease (AD), while effective i... more Existing cholinesterase (ChE) inhibitor therapies for Alzheimer's disease (AD), while effective in improving cognitive, behavioral and functional impairments, do not alter disease progression. Novel drug design studies have focused on the classical ChE inhibitor, (-)-physostigmine, producing alterations in chemical composition and threedimensional structure, which may offer an improved therapeutic index. The phenylcarbamate derivative, (-)-phenserine, is a selective, non-competitive inhibitor of acetylcholinesterase (AChE). In vivo, (-)-phenserine produces rapid, potent, and long-lasting AChE inhibition. As a possible result of its preferential brain selectivity, (-)-phenserine is significantly less toxic than (-)-physostigmine. In studies using the Stone maze paradigm, (-)-phenserine has been shown to improve cognitive performance in both young learning-impaired and elderly rats. In addition to reducing inactivation of acetylcholine in the brain, (-)-phenserine appears to have a second mode of action. Reduced secretion of beta-amyloid (Aβ) has been observed in cell lines exposed to (-)-phenserine, occurring through translational regulation of beta-amyloid precursor protein (β-APP) mRNA via a non-cholinergic mechanism. These in vitro findings appear to translate in vivo into animal models and humans. In a small study of patients with AD, (-)-phenserine treatment tended to reduce β-APP and Aβ levels in plasma samples. Clinical studies also reveal that (-)-phenserine (5-10 mg b.i.d.) had a favorable safety and pharmacological profile, produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks. Further randomized, double-blind, placebo-controlled Phase III studies assessing the efficacy, safety/tolerability and potential disease-modifying effects of (-)-phenserine in patients with AD are currently ongoing.
Molecular Brain Research, 1998
The amyloid b-protein Ab is an approximately 4 kD secreted protein normally found in human plasma... more The amyloid b-protein Ab is an approximately 4 kD secreted protein normally found in human plasma and cerebrospinal fluid. Ab Ž . is invariably deposited as insoluble amyloid fibrils in the brains of patients with Alzheimer's disease AD , and there is increasing evidence that Ab deposition plays an important role in AD pathogenesis. Ab is released from the larger b-amyloid precursor protein Ž . bAPP through cleavage on the amino and carboxyl side of Ab by proteolytic activities referred to as b and g secretase, respectively. bAPP is also cleaved at Ab16 by a third protease, a secretase, which may prevent amyloid deposition by bisecting the Ab peptide. Tacrine, a cholinesterase inhibitor, has been shown to improve memory and cognitive functions in some patients with AD, and we have Ž . previously demonstrated that it significantly reduces the levels of the secretion of soluble bAPP fragments sAPP in cultured cells. In this study, we extended our studies by analysis of Ab40 and Ab42 and report that in a human neuroblastoma cell line tacrine reduced the levels of total Ab, Ab40 and Ab42 in addition to sAPP. These inhibitory results cannot be attributed to a reduction in total bAPP synthesis as tacrine treatment did not cause a significant change in the rate of bAPP synthesis. Furthermore, significant toxicity was not Ž . observed in tacrine-treated cultures as determined by analysis of lactate dehydrogenase LDH in the conditioned media. Taken together, these results suggest that tacrine affects the processing of bAPP by alterations in bAPP trafficking andror increased intracellular proteolysis. This study raises the possibility that tacrine may aid in the treatment of AD due to its effects on bAPP processing as well as by its effects on the cholinergic pathway. q 1998 Elsevier Science B.V. All rights reserved.
Current Pharmaceutical Design, 2004
Alzheimer's disease (AD) is characterized by progressive dementia caused by the loss of t... more Alzheimer's disease (AD) is characterized by progressive dementia caused by the loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning and brain deposits of amyloid beta peptide (A beta) and neurofibrillary tangles (NFT). A small fraction of early onset familial AD (FAD) is caused by mutations in genes, such as the beta-amyloid precursor protein (APP) and presenilins that increase the load of A beta in the brain. These studies together with findings that A beta is neurotoxic in vitro, provide evidence that some aggregates of this peptide are the key to the pathogenesis of AD. The yield of A beta and the processing and turnover of APP are regulated by a number of pathways including apolipoprotein E, cholesterol and cholinergic agonists. Early studies showed that muscarinic agonists increased APP processing within the A beta sequence (sAPP alpha). More recently, we have presented evidence showing that some, but not all, anticholinesterases reduce secretion of sAPP alpha as well as A beta into the media suggesting that cholinergic agonists modulate A beta levels by multiple mechanisms. Herein we review the recent advances in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. We propose and support the position that the influence of cholinergic stimulation on amyloid formation is critical in light of the early targeting of the cholinergic basal forebrain in AD and the possibility that maintenance of this cholinergic tone might slow amyloid deposition. In this context, the dual action of certain cholinesterase inhibitors on their ability to increase acetylcholine levels and decrease amyloid burden assumes significance as it may identify a single drug to both arrest the progression of the disease as well as treat its symptoms. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. We critically discuss recent trends in AD research, from molecular and genetic to clinical areas, as it relates to the effects of cholinergic agents and their secondary effects on A beta. Finally, we examine different neurobiological mechanisms that provide the basis of new targets for AD drug development.
International Psychogeriatrics, 2002
Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE)... more Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lend to a wider variety of potent treatment options.
Neuromolecular Medicine, 2002
Alzheimer’s disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa ... more Alzheimer’s disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39–42 residues known as amyloid beta-peptide (Aβ) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as “secretases” participate in APP processing. An enzymatic activity, β-secretase, cleaves APP on the amino side of Aβ producing a large secreted derivative, sAPPβ, and an Aβ-bearing membrane-associated C-terminal derivative, CTFβ, which is subsequently cleaved by the second activity, γ-secretase, to release Aβ. Alternatively, a third activity, α-secretase, cleaves APP within Aβ to the secreted derivative sAPPα and membrane-associated CTFα. The predominant secreted APP derivative is sAPPα in most cell-types. Most of the secreted Aβ is 40 residues long (Aβ40) although a small percentage is 42 residues in length (Aβ42). However, the longer Aβ42 aggregates more readily and was therefore considered to be the pathologically important form. Advances in our understanding of APP processing, trafficking, and turnover will pave the way for better drug discovery for the eventual treatment of AD. In addition, APP gene regulation and its interaction with other proteins may provide useful drug targets for AD. The emerging knowledge related to the normal function of APP will help in determining whether or not the AD associated changes in APP metabolism affect its function. The present review summarizes our current understanding of APP metabolism and function and their relationship to other proteins involved in AD.
Journal of Pharmacology and Experimental Therapeutics, 2006
Major characteristics of Alzheimer&am... more Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid beta-peptide (Abeta), a proteolytic fragment of amyloid beta precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe Abeta-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Abeta. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (+)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose- and time-dependently lowered APP and Abeta levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. Abeta40 and Abeta42 levels were significantly lowered by posiphen (> or =15 mg/kg) compared with controls. The activities of alpha-, beta-, and gamma-secretases were assessed in the same brain samples, and beta-secretase activity was significantly reduced. Posiphen, like phenserine, can lower Abeta via multiple mechanisms and represents an interesting drug candidate for AD treatment.
Faseb Journal, 2004
The aims of this study are 1) to functionally characterize regulatory domains within the BACE gen... more The aims of this study are 1) to functionally characterize regulatory domains within the BACE gene (i.e., to understand regulation of BACE expression); 2) to examine regulatory domains within the BACE gene; 3) to determine expression levels of BACE regulatory regions in different cell types; 4) to investigate whether the BACE promoter region binds to cell-type specific proteins; and 5) to examine how the BACE gene is regulated by different transcription factors.
Molecular Brain Research, 1991
The nucleus basalis of Meynert was lesioned by infusion of N-methyl-o-aspartate (NMDA) unilateral... more The nucleus basalis of Meynert was lesioned by infusion of N-methyl-o-aspartate (NMDA) unilaterally in adult rat brain. Seven days post lesion we observed that polysomes isolated from the cerebral cortex affected by the lesion synthesized 2.6-fold greater amounts of the Alzheimer amyloid precursor protein (AAPP) compared to the nonlesioned side of the same rat brain. This increase exhibited specificity to AAPP in that overall protein synthesis was not altered by the lesion. The increase of AAPP did not alter the ratio of AAPP isotypes in rat brain (in which AAPP 695, which is lacking the protease inhibitor insert remains the predominant form). The increased synthesis did not result in the apparent accumulation of mature AAPP. These results indicate that a cholinergic lesion which models many of the neurochemical changes observed in Alzheimer's disease induces the expression of AAPP in a major projection region, the cerebral cortex.
Molecular Brain Research, 1991
The nucleus basalis of Meynert was lesioned by infusion of N-methyl-o-aspartate (NMDA) unilateral... more The nucleus basalis of Meynert was lesioned by infusion of N-methyl-o-aspartate (NMDA) unilaterally in adult rat brain. Seven days post lesion we observed that polysomes isolated from the cerebral cortex affected by the lesion synthesized 2.6-fold greater amounts of the Alzheimer amyloid precursor protein (AAPP) compared to the nonlesioned side of the same rat brain. This increase exhibited specificity to AAPP in that overall protein synthesis was not altered by the lesion. The increase of AAPP did not alter the ratio of AAPP isotypes in rat brain (in which AAPP 695, which is lacking the protease inhibitor insert remains the predominant form). The increased synthesis did not result in the apparent accumulation of mature AAPP. These results indicate that a cholinergic lesion which models many of the neurochemical changes observed in Alzheimer's disease induces the expression of AAPP in a major projection region, the cerebral cortex.
Molecular Brain Research, 1991
The nucleus basalis of Meynert was lesioned by infusion of N-methyl-o-aspartate (NMDA) unilateral... more The nucleus basalis of Meynert was lesioned by infusion of N-methyl-o-aspartate (NMDA) unilaterally in adult rat brain. Seven days post lesion we observed that polysomes isolated from the cerebral cortex affected by the lesion synthesized 2.6-fold greater amounts of the Alzheimer amyloid precursor protein (AAPP) compared to the nonlesioned side of the same rat brain. This increase exhibited specificity to AAPP in that overall protein synthesis was not altered by the lesion. The increase of AAPP did not alter the ratio of AAPP isotypes in rat brain (in which AAPP 695, which is lacking the protease inhibitor insert remains the predominant form). The increased synthesis did not result in the apparent accumulation of mature AAPP. These results indicate that a cholinergic lesion which models many of the neurochemical changes observed in Alzheimer's disease induces the expression of AAPP in a major projection region, the cerebral cortex.
Neuroscience Letters, 1991
We have identified the secretory cleavage site in the Alzheimer amyloid precursor (APP) in a non-... more We have identified the secretory cleavage site in the Alzheimer amyloid precursor (APP) in a non-transfected neuronal cell line, using cyanogen bromide digests of APP purified from medium conditioned by PC-12 cells which were differentiated to a neuronal phenotype. The results obtained are most consistent with proteolysis of the Lys16-Leu17 bond in the beta amyloid peptide, followed by partial removal of Lys16 by a basic carboxypeptidase.
Journal of Molecular Neuroscience, 2003
An integral membrane aspartyl protease, BACE, is responsible for β-secretase processing of the β-... more An integral membrane aspartyl protease, BACE, is responsible for β-secretase processing of the β-amyloid precursor protein (APP) to the large secreted sAPPβ and membrane-bound CTFβ of 99 residues. CTFβ is subsequently cleaved within the membrane by γ-secretase to the amyloid β protein (Aβ) that is deposited in the Alzheimer’s disease (AD) brain. In this manuscript, we argue that BACE is not limiting for Aβ production and report the existence of a high molecular weight complex of BACE that is more active than the monomer. We also present evidence that the BACE complex is enriched in lipid raft fractions prepared from brain membranes. These findings support the hypothesis that cleavage by BACE is limited by trafficking of APP (
Journal of Neuroscience Research, 1994
Phorbol esters (PDBu) stimulate α-secretase cleavage and secretion of the Alzheimer amyloid precu... more Phorbol esters (PDBu) stimulate α-secretase cleavage and secretion of the Alzheimer amyloid precursor protein (APP). To determine whether any cytoplasmic residues or sequence motifs mediate the PDBu effect on APP processing, this region of APP was altered by point mutations or deletions. To differentiate the mutated APP from the endogenous APP, the APP751 ectodomain between amino acids 1 and 647 was replaced by a human secreted alkaline phosphatase derivative (SEAP). The resultant fusion protein (SEAP-APP751) was cleaved by α-secretase at the same site as full-length APP, and its secretion was stimulated by PDBu at a level similar to APP751. However, PDBu-stimulated secretion of the SEAP-APP751 fusion protein reached its maximum level after 30 min of treatment, while secretion of APP751 reached its maximum after 60 min, suggesting that the APP ectodomain affects the kinetics of APP secretion.Mutation of the cytoplasmic serines to alanines had no effect on the PDBu-stimulated secretion of the SEAP-APP, indicating that protein kinase C (PKC) phosphorylation of the cytoplasmic domain of APP is not important for stimulation of APP secretion. Similarly, deletion of the cytoplasmic domain between amino acids 719 and 751 had no effect on the PDBu-stimulated secretion. However, deletion of amino acids 707–751 resulted in a significant increase in the secretory cleavage of the SEAP-APP707ΔC construct, suggesting that the sequence 707–719 is important for the regulated secretion of APP.Cholera toxin, but not pertussis toxin, reduced the PDBu-induced secretion of APP by more than two-fold, suggesting that the PDBu response may be modulated by a cholera toxin sensitive heterotrimeric G-protein. © 1994 Wiley-Liss, Inc.
Journal of Neuroscience Research, 1995
Three different treatments (methylamine, colchicine, and 18°C temperature block), known to disrup... more Three different treatments (methylamine, colchicine, and 18°C temperature block), known to disrupt normal endocytic internalization, significantly reduced the secretory cleavage of cell surface-derived Alzheimer amyloid precursor (APP) in non-transfected C6 cell cultures. Conversely, treatments with methylamine or colchicine had no significant effect on the secretion of total APP. Treatment of these cells with the lysosomotropic amine chloroquine resulted in a significant increase in the levels of both cell surface full-length APP and cell surface-derived secreted nexin II (NXII). Immunofluorescence analysis of C6 glioma cells transfected with APP751 indicated that under normal conditions, cell surface APP was internalized, and within 30 minutes was localized in discrete intracellular vesicles. These vesicles contained the endocytic tracer Texas red-conjugated ovalbumin and probably represented late endosomes or lyso-somes. However, treatment of the transfected C6 cultures with methylamine or colchicine prevented localization of cell surface APP in intracellular vesicles, suggesting that these treatments altered the normal intracellular trafficking of cell surface-derived APP. Both the biochemical and immunofluorescence data are compatible with the suggestion that inhibition of normal endocytic internalization reduces the secretory cleavage of cell surface APP. Furthermore, our results suggest that following internalization, cell surface APP is cleaved by secretase(s) and secreted or routed to the lysosomes where it is degraded. © 1995 Wiley-Liss, Inc.
Neurobiology of Disease, 2006
Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may incr... more Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (AB) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBS tm1Unc mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of AB40 and AB42 levels in the brain. Correlations between homocysteine levels in serum and brain AB levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found.
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Papers by Kumar Sambamurti