Investigating the Role of Aging and Pathological Tau in Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by accumulation of plaques made of insoluble beta-amyloid protein, neurofibrillary tangles containing hyperphosphorylated tau protein, and neuronal damage leading to neuronal death. In order to offer better prognoses for individuals affected by AD, more research needs to be conducted to (a) understand risk factors that enhance the development of AD and/or exacerbate its symptoms and (b) assess detrimental alterations that occur in the earliest brain regions to be impacted in AD, such as the entorhinal cortex (EC). First, we utilized a regulatable transgenic model to specifically assess the impact of AD pathology in an aged brain on pathology-induced cognitive deficits, glutamatergic signaling, and detrimental protein alterations to address problem A. To assess problem B, we directly delivered mutant tau protein to the EC of otherwise healthy mice in order to assess the impact of EC-pathological tau on cognitive performance, basal synaptic transmission, glutamate release, and long-term potentiation. In addition, we utilized the optogenetic technique to manipulate neuronal activity in the EC in the context of tau pathology in order to assess the interplay between changes in neuronal activity in pathological tau spread, associated cognitive deficits, and detrimental alterations in protein expression.