Development of Region-Specific Tau Pathology in P301S Mice Open Access

McCann, Ryan (Spring 2020)

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Alzheimer’s disease (AD) is a common neurodegenerative disease that is characterized by two main pathologies: the aggregation of tau protein into neurofibrillary tangles (NFT) and the aggregation of amyloid precursor protein fragments into amyloid-b(Ab) plaques. This project focuses on tau pathology, which is more strongly correlated with the neurodegeneration and cognitive impairment in AD. In humans, tau pathology can first be detected in a vulnerable brainstem region, the noradrenergic locus coeruleus (LC), before appearing in the forebrain later in disease progression. The goal of this project was to determine whether this time-dependent pattern of tau pathology is recapitulated in the P301S transgenic mouse, a popular rodent model of AD-like tauopathy that overexpresses an aggregation-prone mutant form of human tau. The transgene promoter used to produce these mice (mouse prion promoter) is expressed simultaneously in the brainstem and forebrain, suggesting that tau pathology may develop in all neurons at a similar time. However, due to several intrinsic vulnerabilities of LC neurons, we hypothesized that tau pathology would first develop in the LC, and then in downstream memory regions such as entorhinal cortex (EC) and hippocampus (HC). To determine the order of pathology development in each brain region in P301S mice, we used immunofluorescence to detect hyperphosphorylated tau, an early form of pathology, at 1-2, 3-4, 5-6 and 7-8 months of age. We found that the first brain region to show a significant level of tau pathology compared to wild-type control was the CA3 region of the HC (1-2 months), followed by the LC and dentate gyrus region of the HC (3-4) months, the EC (5-6 months), and finally the CA1 region of the HC (7-8 months). Thus, while there was selective region vulnerability in P301S mice, they did not demonstrate the progression of tau pathology seen in human AD. 

Table of Contents

Introduction    Page 1

Hypothesis      Page 5

Methods          Page 5

Results            Page 7

Discussion      Page 14

References      Page 19

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