Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments, which has become the sixth leading cause of death in the United States (www.alz.org) [1,2]. Individuals with AD develop brain atrophy and neuronal loss, and the disease is characterized by the presence of dense extracellular deposits of amyloid plaques and neurofibrillary tangles [3–14]. Much of our understanding of the mechanisms underlying AD pathology comes from a population of individuals with early-onset familial AD (fAD). These cases harbor causal mutations involving primarily the Aβ processing enzymes, presenilin 1 and 2 (PSEN1, PSEN2), which are part of the γ-secretase complex [15–18] [15–18], or mutations within or duplications of the amyloid precursor protein (APP) gene itself [19–22]. Neurofibrillary tangles are comprised of intraneuronal accumulations of the microtubule-associated protein tau [19]. Tau pathology (tauopathy), consisting of aberrantly phosphorylated (pTau) and aggregated tau, is characteristic of a number of neurodegenerative disorders, including AD [23–25]. The extent of tau pathology in human AD has been shown to correlate well to cognitive impairment [26]. Many studies have shown that the aberrant phosphorylation and aggregation of tau underlie tauopathy in human brain and animal models.
