title: Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease.
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.
authors.affiliation: 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. [2] Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA. [3] Program in Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Usman A
authors.initials: UA
authors.lastname: Khan
authors.affiliation: 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. [2] Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: 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. [2] Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Provenzano
authors.affiliation: 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. [2] Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Diego E
authors.initials: DE
authors.lastname: Berman
authors.affiliation: 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. [2] Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Caterina P
authors.initials: CP
authors.lastname: Profaci
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sloan
authors.affiliation: 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. [2] Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: 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. [2] Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Duff
authors.affiliation: 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. [2] Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, USA. [3] Department of Radiology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Small
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001931:Brain Mapping; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D013181:Cortical Spreading Depression / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D018728:Entorhinal Cortex / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007839:Functional Laterality / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D016875:tau Proteins; D010100:Oxygen