Manipulation of neuronal activity in the entorhinal-hippocampal circuit affects intraneuronal amyloid-β levels
One of the neuropathological hallmarks of Alzheimers disease (AD) is the accumulation of amyloid-{beta} (A{beta}) plaques, which is preceded by intraneuronal build-up of toxic, aggregated A{beta} during disease progression. A{beta} plaques are first deposited in the neocortex before appearing in the medial temporal lobe, and tau pathology with subsequent neurodegeneration in the latter anatomical region causes early memory impairments in patients. Current research suggests that early intraneuronal A{beta} build-up may begin in superficial layers of lateral entorhinal cortex (LEC). To examine whether manipulation of neuronal activity of LEC layer II neurons affected intraneuronal A{beta} levels in LEC and in downstream perforant path terminals in the hippocampus (HPC), we used a chemogenetic approach to selectively and chronically silence superficial LEC neurons in young and aged 3xTg AD mice and monitored its effect on intraneuronal A{beta} levels in LEC and HPC. Chronic chemogenetic silencing of LEC neurons led to reduced early intraneuronal A{beta} in LEC and in projection terminals in the HPC, compared with controls. Early intraneuronal A{beta} levels in the downstream HPC correlated with activity levels in superficial layers of LEC, with the subiculum being the earliest subregion involved, and our findings give evidence to early AD neuropathology originating in select neuronal populations.