Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are the major pathological features in an Alzheimer’s brain. These proteins are highly expressed in nerve cells and found in most tissues. Tau primarily provides stabilization to microtubules in the part of axons and dendrites. However, tau in a pathological state becomes hyperphosphorylated, causing tau dysfunction and leading to synaptic impairment and degeneration of neurons. This article presents a summary of the role of tau, phosphorylated tau (p-tau) in AD, and other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, Alzheimer’s disease, argyrophilic grain disease, progressive supranuclear palsy, and Huntington’s disease, are the result of misprocessing and accumulation of tau within the neuronal and glial cells. This article also focuses on current research on the post-translational modifications and genetics of tau, tau pathology, the role of tau in tauopathies and the development of new drugs targeting p-tau, and the therapeutics for treating and possibly preventing tauopathies.

The past and present of therapeutic strategy for Alzheimer’s diseases: potential for stem cell therapy

“…Under physiological conditions, tau is expressed mainly in neurons and contributes to microtubule stabilization [63,64]. Intracellular hyperphosphorylated tau protein self-aggregates to form paired helical and tightly-wrapped straight filaments, causing the formation of NFTs in neural cells [12,13]. NFTs represent cell-type-specific responses, such as stress, synaptic dysfunction, and neural cell death, in patients with AD [65].…”

“…Intracellular hyperphosphorylated tau protein causes the formation of neurofibrillary tangles (NFTs) in neural cells [12,13] Both SPs and NFTs are typical neuropathological hallmarks of patients with AD [14]. Abnormal amyloid and tau have been reported as risk factors for future cognitive decline in individuals with normal cognition [15].…”

Therapeutics of Alzheimer’s Disease: Recent Developments

“…Tau is a microtubule-associated protein that helps the brain stabilize axonal microtubules, but an abnormal deposition of this protein leads to various diseases, including dementia [ 60 ]. The pathogenesis of tau is represented in Figure 5 .…”

“…The effectiveness of tau immunotherapies was first reported in the JNPL3 mouse model in 2007, which showed remarkably less tau pathology in different brain regions [ 63 ]. Currently, most tau-targeted therapies in preclinical trials are immunotherapies [ 60 ].…”

“…ACI 35: This liposome-based vaccine contains 16 copies of synthetic tau fragments phosphorylated at phosphorylation sites at S396 and S404 and is anchored into a lipid bilayer to activate the immune system to produce antibodies [ 60 ]. In July 2019, AC Immune and Janssen started a small phase 1b/2a trial to test the safety and immunogenicity of ACI-35 in people with early AD.…”