Role of Tau Protein in Neuronal Damage in Alzheimer's Disease and Down Syndrome

Abstract

Neurodegenerative disorders constitute a growing concern worldwide. Their incidence has increased steadily, in particular among the elderly, a high-risk population that is becoming an important segment of society. Neurodegenerative mechanisms underlie many ailments such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease (AD) and Down syndrome (DS, trisomy 21). Interestingly, there is increasing evidence suggesting that many such diseases share pathogenic mechanisms at the cellular and subcellular levels. These include altered protein misfolding, impaired autophagy, mitochondrial dysfunction, membrane damage, and altered axonal transport. Regarding AD and DS, the first common link comes from observations that DS patients undergo ADlike pathology early in adulthood. Also, the gene encoding for the amyloid precursor protein is present in human autosome 21 and in murine chromosome 16, an animal model of DS. Important functions related to preservation of normal neuronal architecture are impaired in both conditions. In particular, the stable assembly of microtubules, which is critical for the cytoskeleton, is impaired in AD and DS. In this process, tau protein plays a pivotal role in controlling microtubule stability. Abnormal tau expression and hyperphosphorylation are common features in both conditions, yet the mechanisms leading to these phenomena remain obscure. In the present report we review possible common mechanisms that may alter tau expression and function, in particular in relation to the effect of certain overexpressed DS-related genes, using cellular models of human DS. The latter contributes to the identification of possible therapeutic targets that could aid in the treatment of both AD and DS.