Paired helical filaments (PHFs) are the major building blocks of neurofibrillary lesions in Alzheimer's disease brains and are composed of hyperphosphorylated tau protein. Predominantly expressed in axons, alternatively spliced forms of tau comprise a family of microtubule-associated proteins that normally promote and stabilize the assembly of microtubules. PHF-tau differs from normal tau by its abnormal hyperphosphorylation, which results in decreased binding of tau to microtubules. The decreased affinity of PHF-tau for microtubules, coupled with reduced levels of normal tau, destabilizes microtubules leading to an impairment of axonal transport, neuronal death and the aggregation of PHFs. Therefore, hyperphosphorylation of tau is believed to be a key event in the pathogenesis of Alzheimer's disease.
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