[14][15][16] Although tau is present in dendrites at low levels, where it is involved in postsynaptic scaffolding,[17] it is active primarily in the distal portions of axons, where it provides microtubule stabilization but also flexibility as needed.

In addition to its microtubule-stabilizing function, Tau has also been found to recruit signaling proteins and to regulate microtubule-mediated axonal transport.

In mice, while the reported tau knockout strains present without overt phenotype when young,[14][23][24] when aged, they show some muscle weakness, hyperactivity, and impaired fear conditioning.

In addition, tau knockout mice have abnormal sleep-wake cycle, with increased wakefulness periods and decreased non-rapid eye movements (NREM) sleep time.

Uptake of tau protein requires the presence of heparan sulfate proteoglycans at the cell surface, which happens by macropinocytosis.

[50] According to Asai and his colleagues, the spreading of tau protein occurs from the entorhinal cortex to the hippocampal region in the early stages of the disease.

This enzyme stimulates phosphorylation of serine 262 and 356, which in turn leads to activate other kinases (GSK-3 and CDK5) that cause disease-associated phosphoepitopes.

[58] All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments in the Alzheimer's disease brain.

When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.

Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nerve synapses.

All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments (PHFs) in the AD brain.

The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans.

This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.

[65][59] Hyperphosphorylated forms of tau protein are the main component of PHFs of NFTs in the brain of AD patients.

[66] Hyperphosphorylated tau differs in its sensitivity and its kinase as well as alkaline phosphatase activity[67] and is, along with beta-amyloid, a component of the pathologic lesion seen in Alzheimer disease.

[70] A68 is a name sometimes given (mostly in older publications) to the hyperphosphorylated form of tau protein found in the brains of individuals with Alzheimer's disease.

[71] In 2020, researchers from two groups published studies indicating that an immunoassay blood test for the p-tau-217 form of the protein could diagnose Alzheimer's up to decades before dementia symptoms were evident.

[72][73][74] Repetitive mild traumatic brain injury (TBI) is a central component of contact sports, especially American football,[75][76] and the concussive force of military blasts.

[77] It can lead to chronic traumatic encephalopathy (CTE), a condition characterized by fibrillar tangles of hyperphosphorylated tau.

[79] The term "prion-like" is often used to describe several aspects of tau pathology in various tauopathies, like Alzheimer's disease and frontotemporal dementia.