The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

Abstract

Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become the focus of therapeutic development. Recent research, however, shows that these proteins have been highly conserved throughout evolution and may have crucial, physiological roles. Such functions may be lost during AD progression or be unintentionally disrupted by tau- or Aβ-targeting therapies. Tau has been revealed to be more than a simple stabiliser of microtubules, reported to play a role in a range of biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning and memory, neuronal excitability, and DNA protection. Aβ is similarly multifunctional, and is proposed to regulate learning and memory, angiogenesis, neurogenesis, repair leaks in the blood–brain barrier, promote recovery from injury, and act as an antimicrobial peptide and tumour suppressor. This review will discuss potential physiological roles of tau and Aβ, highlighting how changes to these functions may contribute to pathology, as well as the implications for therapeutic development. We propose that a balanced consideration of both the physiological and pathological roles of tau and Aβ will be essential for the design of safe and effective therapeutics.

Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

“…Thus, Aβ should be considered firstly as a physiological product derived from normal processing of APP ( 78 , 79 ). Although little is still known about the exact physiological role of Aβ, the peptide is known to regulate synaptic activity, to have antimicrobial and tumor suppressing properties (for review see ( 80 )), and to be neuroprotective in some pathological conditions ( 81 , 82 , 83 ). Thus, to some extent the failure of clinical trials aimed at either inhibiting Aβ production or neutralizing Aβ once formed could be explained, at least in part, by the abolition of such Aβ-mediated physiological functions.…”

An Ensemble-Learning Based Application to Predict the Earlier Stages of Alzheimer’s Disease (AD)

“…The candidate protein biomarker (Cystatin C, MMP10, and tau proteins) screened in this study belongs to different pathways and a functional group whose association with AD pathophysiology has been investigated and documented, most notably, tau protein, a traditional CSF biomarker which has proven useful in the diagnosis and prognosis of AD. In some individuals with a very MCI, CSF tau levels have shown gradual increase years before being ultimately diagnosed with AD [15][16][17]. Therefore, the tau protein has been useful for predicting AD's onset in individuals with very mild or mild cognitive disorders.…”

“…Thus, for the early detection of AD, identifying specific biomarkers that play a significant role in converting MCI to AD has become of great interest in recent times [11][12][13][14]. In the current scenario, conventional CSF biomarkers, namely tau, amyloid-β42 (Aβ42), and phosphorylated forms of tau (p-tau), have shown more significant potential in the screening of MCI patients who eventually progressed to clinically diagnosable AD [15][16][17][18][19].…”

Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review

“…ARTAG and severe (advanced-stage) CTE are astrocytopathies characterized by astrocytic tau inclusions. The normal functions of tau protein are debated [24][25][26] and the roles for tau proteins in glial cells are mostly unknown. In the adult human brain, six tau isoforms are generated by alternative splicing of the microtubule associated protein tau (MAPT) gene.…”