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Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease
Open accessAbstract
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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“the hippocampal region is important to short-term memory loss in AD and is the earliest region involved in the progression of the disease”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [40]
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Metadata
- Authors
- Khan, U. A., Liu, L., Provenzano, F. A., Berman, D. E., Profaci, C. P., Sloan, R., Mayeux, R., Duff, K. E., & Small, S. A.
- Affiliations
- SUNY Downstate Health Sciences University (US)
- Columbia University (US)
- Corresponding author
- Duff, Karen E
- Small, Scott A
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2013-12-22
- Volume
- 17
- Issue
- 2
- Pages
- 304-311
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4044925
- OpenAlex
- W1966100017
- Cited by
- 561
- References
- 60
- Citations by year
- 2026: 23 · 2025: 33 · 2024: 38 · 2023: 52 · 2022: 56 · 2021: 48 · 2020: 51 · 2019: 54 · 2018: 59 · 2017: 54 · 2016: 36 · 2015: 31 · 2014: 23 · 2013: 1
- FWCI
- 21.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Ministerio de Economía y Competitividad
- National Institute on Aging (R01AG034618, R01AG037212, P01AG007232, AG 07232, AG025161, R01AG025161, P50AG008702, AG037212, AG034618)
- National Heart, Lung, and Blood Institute (R01HL094423, HL094423)
- National Institute of Neurological Disorders and Stroke (NS074874, R01NS074874)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007430)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- preclinical Alzheimer's disease, lateral entorhinal cortex, medial entorhinal cortex, amyloid precursor protein, tau protein, parietal cortex, regional vulnerability, mouse models of Alzheimer's disease
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Animals, Brain Mapping, Cognition Disorders, Female, Humans, Image Processing, Computer-Assisted, Functional Laterality, Magnetic Resonance Imaging, Male, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Oxygen, Cortical Spreading Depression, Gene Expression, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Disease Progression, Entorhinal Cortex, Mice
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