Tau-mediated neurodegeneration in Alzheimer’s disease
Tau acetylation causes increased tau aggregation in vitro and promotes the formation of tau tangles observed in AD brain (Cohen et al., Nat Commun, 2011).
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. With an increase in ageing among the human population, we are currently faced with a looming AD epidemic unless we explore new therapeutic options that target the underlying basis of this disease. The signature brain lesions found in Alzheimer’s disease are plaques composed of the Ab protein and neurofibrillary tangles (NFTs) composed of the tau protein. In both cases, abnormal accumulation and clumping of these proteins occurs in AD brain leading to impaired neuron function and subsequent neurodegenerative symptoms including dementia. Therefore, if we can prevent the abnormal clumping, or aggregation, of these proteins using specific drugs, then we could potentially provide therapies to prevent neurodegeneration and the onset or progression of AD. To accomplish such a challenging feat, we require a careful understanding of the mechanisms that dictate protein aggregation in the diseased brain. Such information will provide the framework to understand the pathogenesis of Alzheimer’s disease.
One way to control protein function is via post-translational modifications (PTMs), which are chemical tags that allow proteins to navigate and communicate with their surrounding environment within a cell. One such modification referred to as acetylation can be chemically attached to a specific amino acid (i.e. lysine) present within the proteins in the brain. Importantly, acetylation can often result in abnormal alterations in protein functions, including the clumping similar to that observed in AD brain. Remarkably, we have recently discovered that acetylation of normal tau protein can transform tau into clumpy aggregates, also known as fibrils, that resemble the hallmark lesions observed in Alzheimer’s brain. Therefore, we speculate that abnormal acetylation in the brain can drive the formation tau clumps and subsequent neurodegenerative symptoms.