Year: 2009
Type: article
Abstract: Most mouse models developed to study tau pathology in Alzheimer's disease (AD) rely on mutant tau transgenes to generate neurofibrillary pathology (NFT). Mutant tau has distinct biologic properties not seen in endogenous tau, such as enhanced fibrillogenesis, while it is the endogenous form of tau that is deposited in NFTs in AD. Although mutant constructs of APP lead to amyloid deposits similar to endogenous amyloid, a wild-type tau model is required to produce more AD-like tau pathology. We have generated such a model (mTau) by overexpressing genomic mouse tau. The importance of a wild-type tauopathy model is underlined by published data showing that reducing endogenous tau in an APP model reduces the Abeta-induced AD phenotype. The purpose of this study is to reproduce key features of AD, amyloid and hyperphosphorylated non-mutant tau pathology, by crossing our mTau model with an appropriate APP model for AD. We present pathological characterization of brains from transgenic (Tg), bigenic and non-transgenic (NTg) animals using immunohistochemistry to detect Abeta, hyperphosphorylated tau, and NeuN as a neuronal marker. An Aperio slide scanner and ImageScope image analysis software were used to measure burden. Our transgenic wild-type mouse tau model shows hyperphosphorylated tau accumulation, gliosis, and vacuolization with age. Image analysis also shows hippocampal neuronal loss in the mTau mice. At 3 months of age mTau/APP bigenic animals show an increase in hyperphosphorylated tau immunoreactivity compared to NTg and single transgenic (Tg) littermates. The burden of Abeta plaques is similar in bigenic animals and single Tg littermates. In contrast, tau burden is greater in bigenic 3 month old animals compared to 15 month old mTau mice. Our mTau model develops abnormal tau and other pathologies similar to that of early stage AD. The pathology results from the mTau/APP mice suggest that overexpression of APP and endogenous tau produces a pronounced phenotype. This model will provide the first overexpressing wild-type tau/APP model available for the study of AD. Understanding the pathogenesis of amyloid and neurofibrillary pathology in this more relevant AD model will therefore provide a more appropriate system for analysis of potential therapeutic targets.
Source: Alzheimer s & Dementia
Institutions: Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2061808546