Transsynaptic Progression of Amyloid-β-Induced Neuronal Dysfunction within the Entorhinal-Hippocampal Network

• DOI: 10.1016/j.neuron.2010.10.020
• Publication Date: 2010-11-04T08:18:23Z
• Authors: Julie A. Harris; Nino Devidze; Laure Verret; Kaitlyn Ho; Brian Halabisky; Myo T. Thwin; Daniel Kim; Patricia Hamto; Iris Lo; Gui-Qiu Yu; Jorge J. Palop; Eliezer Masliah; Lennart Mucke
• Keywords: Neuroscience(all); Mice, Transgenic; In Vitro Techniques; Hippocampus; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Memory; Animals; Entorhinal Cortex; Humans; Calcium Signaling; Maze Learning; Amyloid beta-Peptides; Behavior, Animal; Electroencephalography; Immunohistochemistry; Mice, Inbred C57BL; Disease Progression; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Amyloid Precursor Protein Secretases; Cognition Disorders

The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer's disease (AD), which is associated with amyloid-β (Aβ) accumulation in many brain areas. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. APP/Aβ overexpression in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1 and epileptiform activity in parietal cortex. Soluble Aβ was observed in the dentate gyrus, and Aβ deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Aβ expression in EC neurons causes transsynaptic deficits that could initiate the cortical-hippocampal network dysfunction in mouse models and human patients with AD.