Tau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction

Abstract

Alzheimer's disease (AD) is characterized by two pathological features: neurofibrillary tangles (NFTs), formed by microtubule-associated protein tau, and abnormal accumulation of amyloid-β (Aβ). Multiple evidence placed synaptic tau as the vital fact of AD pathology, especially at the very early stage of AD. In the present review, we discuss tau phosphorylation, which is critical for the dendritic localization of tau and synaptic plasticity. We review the related kinases and phosphatases implicated in the synaptic function of tau. We also review the synergistic effects of these kinases and phosphatases on tau-associated synaptic deficits. We aim to open a new perspective on the treatment of AD.

Atomic Force Microscopy Applied to the Study of Tauopathies

“…These interactions can result in tau hyperphosphorylation and its detachment from microtubules. 116 Even though the phosphorylation process is the most responsible for tau aggregation, other post-translational modifications can also be observed, such as acetylation, glycation, glycosylation with O-linked N-acetylglucosamine (O-GlcNAcylation), ubiquitination, and truncation. 117−121 After these alteration processes, the physiological functions of tau are lost, resulting in cellular damages such as loss of microtubule dynamics and cleavage, "traffic jam" of axonal transport proteins, inability to propagate action potentials in neurons, loss of plasticity and early neuronal death, demyelination, oxidative stress, toxic accumulation of iron in the cytoplasm and central insulin resistance.…”

“…Tau might first misfold in tauopathies, becoming an excellent target substrate for kinase enzymes and a poor one for phosphatases. These interactions can result in tau hyperphosphorylation and its detachment from microtubules . Even though the phosphorylation process is the most responsible for tau aggregation, other post-translational modifications can also be observed, such as acetylation, glycation, glycosylation with O-linked N -acetylglucosamine (O-GlcNAcylation), ubiquitination, and truncation. − …”

Exosomal Dynamics and Brain Redox Imbalance: Implications in Alzheimer’s Disease Pathology and Diagnosis

“…Several kinases, namely Glycogen synthase kinase 3β (GSK3β) and Cyclin Dependent Kinase 5 (CDK5), can phosphorylate Tau, while phosphatases, such as Protein phosphatase 2A (PP2A), PP1 and PP2B, may remove phosphate groups from it. Elevated activities of GSK3β and CDK5, together with diminished PP2A activity, seem to be responsible for the increased Tau phosphorylation seen in AD [ 68 , 69 ]. Nevertheless, the factors behind these changes in kinase and phosphatase activity in AD are still not well understood.…”

Alzheimer's Disease: Status of Low‐Dimensional Nanotherapeutic Materials

“…The C terminal folds on the microtubule-binding domain, and the N terminal folds back to the C terminal, forming the Tau "paperclip" conformation. [62] Excessive phosphorylation caused by the abnormal activity of protein kinase and phosphatase, [63][64] the "paperclip" conformation loosens and the tightens. This decreases the binding affinity of Tau to microtubules, leading to its dissociation from microtubules and accelerating normal cells' death.…”