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Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease

Nature Neuroscience volume 17, pages 304–311 (2014)Cite this article

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Abstract

The entorhinal cortex has been implicated in the early stages of Alzheimer's disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer's disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.

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Figure 1: Whole-brain ROI analysis identified dysfunction in the entorhinal cortex and other cortical regions in preclinical Alzheimer's disease.
Figure 2: Voxel-based analysis pinpoints dysfunction in preclinical Alzheimer's disease to the LEC.
Figure 3: The LEC is affected by tau and APP coexpression and leads to cortical dysfunction.
Figure 4: Patterns of cortical spread in mouse models overlap with patterns observed in preclinical Alzheimer's disease.
Figure 5: APP expression acts to potentiate and accelerate tau toxicity in the LEC.
Figure 6: Mapping histological markers of tau and APP in mouse models.
Figure 7: The LEC shows evidence of high metabolism in young unaffected individuals.

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Acknowledgements

This work was supported by US National Institutes of Health grants AG034618 and AG025161 to S.A.S., AG07232 and AG037212 to R.M., NS074874 to K.E.D., and HL094423 to R.S.

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Authors and Affiliations

  1. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Mayeux, Karen E Duff & Scott A Small

  2. Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Usman A Khan, Frank A Provenzano, Richard Mayeux & Scott A Small

  3. Program in Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York, USA

    Usman A Khan

  4. Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Li Liu, Diego E Berman, Caterina P Profaci & Karen E Duff

  5. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Richard Sloan

  6. Department of Radiology, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Scott A Small

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Contributions

U.A.K. performed the mouse and human fMRI analysis and wrote the manuscript. L.L. helped with mouse breeding and performed the histological analyses in mice models. F.A.P. performed the human fMRI post-processing. D.E.B. performed the microarray and other molecular analyses. C.P.P. helped with the histological analyses and mouse breeding. R.S. recruited the young human subjects. R.M. recruited and characterized the older human subjects. K.E.D. supervised the generation and histological analyses in the mouse models and wrote the manuscript. S.A.S. designed the studies, helped with the statistical analyses and wrote the manuscript.

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Correspondence to Karen E Duff or Scott A Small.

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Khan, U., Liu, L., Provenzano, F. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat Neurosci 17, 304–311 (2014). https://doi.org/10.1038/nn.3606

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