A simple spatial navigation paradigm in aging mice connects heterogeneous behavioral phenotypes with neuropathology and Alzheimer’s disease

Abstract

Aging of the brain affects everyone, but some develop signs and symptoms, such as a decline in cognitive function, more quickly than others. Spatial navigation confusion and memory deficits with increasing age may be one of the first indicators of more serious cognitive impairment associated with Alzheimer’s disease (AD). This project was designed to evaluate a spatial navigation learning task coined Boxmaze to predict resistance to AD progression. C57BL/6 female and male mice, 20 months of age, were tested for cognition using the Boxmaze, and then intravenously administered AAV-Aβ42 and AAV-pTau, or an AAV sham vector and followed for two months. Mice were then tested in the Y-maze and retested in the Boxmaze, followed by euthanasia and collection of brain tissues for formalin-fixation and immunohistochemistry using antibodies specific for neuropathology associated aging and AD. A spatial learning index, reflecting individual learning rates, was developed to measure distinctions in cognitive decline. Behavioral data showed that mice had differing susceptibilities to further cognitive decline with correlation of pre-AAV learning index and post-AAV learning index. Cognitive impairment phenotypes were not associated with neuropathology or other aging markers in the brain. Data from this project suggest that the Boxmaze spatial learning index could potentially predict early signs of learning impairment and screen for indicators of resistance or susceptibility to AD.