Abstract
SummaryAlzheimer’s disease (AD) is an age-related neurodegenerative disease with two major hallmarks: extracellular amyloid plaques made of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau. The number of NFTs correlates positively with the severity of dementia in AD patients. However, there is still no efficient therapy available for AD treatment and prevention so far. A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades. Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD. Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders. Abnormal tau hyperphosphorylation plays a detrimental pathological role, eventually leading to neurodegeneration. In the present review, we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.
Highlights
We recently reported that Alzheimer’s disease (AD) O-tau effectively induced tau aggregation in vivo and in vitro in a prion-like manner[67, 70, 129, 130] which can be the amplification and spread basis of tau pathology throughout AD brain
Tau is a central molecule in the AD pathogenesis
Recent studies have shown that tau oligomers, instead of fibrillar aggregates, are cytotoxic through disrupting synaptic function, causing neuronal death and the tau pathology spread in preclinical models of taumediated neurodegeneration in vitro and in vivo[158,159,160]
Summary
1.1 Tau Protein Tau is a neuronal protein associated with microtubules that supports the assembly of tubulins in microtubules and steadies them in the brain. Proline-independent tau S/T residues are phosphorylated by non-PDPKs, including cAMP dependent protein kinase A (PKA), casein kinase 1δ/ε (CK1δ/ε), calcium/calmodulin-activated protein kinase II (CaMKII), microtubule affinity-regulated kinases (MARKs), protein kinase R (PKR) and adenosinemonophosphate activated protein kinase (AMPK)[36,37,38,39,40] PP2A can regulate tau phosphorylation by affecting the functions of other tau protein kinases, including cdk, PKA and CaMKII[17]. 1.3 Tau Truncation
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