P022 - A SWITCH FOR ALZHEIMER’S DISEASE NEUROPATHOLOGY AT ITS REGIONAL ORIGIN (ID 1722)
Abstract
Aims
A major unresolved issue within the Alzheimer’s disease (AD) field includes how neuronal circuits become dysfunctional in response to AD-related neuropathology and how circuit abnormalities can be repaired. The lateral regions of superficial layers in lateral EC entorhinal cortex (LEC LII) is where neuropathology likely begins in AD in terms of neurofibrillary tangles. To determine how particular EC cells may be implicated in preclinical AD and to develop interventions to stop the disease process in these cells, we hypothesized that the projections from LEC LII to the hippocampus might promote a dysfunctional spread of AD neuropathology via excitatory projections.
Methods
Here we initiated pathology by over-expressing mutated human tau (huTau), and chemogenetic receptors in combination with a novel DREADD ligand to chronically inhibit LEC LII neurons to examine the effect on neuropathological development in the hippocampus of 3xTg AD mice.
Results
Our findings indicate that the viral-mediated over-expression of huTau into LEC LII resulted in propagation of huTau from LEC LII to the hippocampus. After longitudinally silencing LEC layer II neurons using hM4 DREADDs we found that AD neuropathology was attenuated in downstream hippocampus, and lead to impairment in a contextual memory task, highlighting the role of the EC-hippocampal network in this type of memory formation.
Conclusions
In conclusion, we have obtained new insights into the origins and mechanisms of neuropathological spread in AD and demonstrate for the first time that amyloid pathology may be spreading in a similar manner to tau during development of the disease.
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