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-beta (A beta) 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/A beta 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 A beta was observed in the dentate gyrus, and A beta deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/A beta expression in EC neurons causes transsynaptic deficits that could initiate the cortical-hippocampal network dysfunction in mouse models and human patients with AD.