Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network.
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.
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Julie A
JA
Harris
Nino
N
Devidze
Laure
L
Verret
Kaitlyn
K
Ho
Brian
B
Halabisky
Myo T
MT
Thwin
Daniel
D
Kim
Patricia
P
Hamto
Iris
I
Lo
Gui-Qiu
GQ
Yu
Jorge J
JJ
Palop
Eliezer
E
Masliah
Lennart
L
Mucke
D000544:Alzheimer Disease / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020013:Calcium Signaling / Q000502:physiology; D003072:Cognition Disorders / Q000523:psychology; D018450:Disease Progression; D004569:Electroencephalography; D018728:Entorhinal Cortex / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000473:pathology*; D009474:Neurons / Q000187:drug effects*; D010641:Phenotype; D058225:Plaque, Amyloid / Q000473:pathology; D013569:Synapses / Q000473:pathology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases