Tau and Alzheimer's disease: Past, present and future

Abstract

My journey with tau started when in 1974 for the first time I isolated neurofibrillary tangles of paired helical filaments (PHFs) from autopsied Alzheimer's disease (AD) brains and discovered that they were made up of a ~50-70 KDa protein on SDS-polyacrylamide gels. Subsequently my team discovered that this PHF protein and the microtubule-associated factor called tau were one and the same protein. However, we found that tau in neurofibrillary tangles/PHFs in AD brain was abnormally hyperphosphorylated, and unlike normal tau, which promoted the assembly of tubulin into microtubules, the AD-hyperphosphorylated tau inhibited microtubule assembly. These discoveries of tau pathology in AD opened a new and a major area of research on tau and on the molecular pathology of this major cause of dementia in middle- and old-age individuals. Tau pathology, which without fail is made up of the aggregated hyperphosphorylated state of the protein, is also the hallmark lesion of a family of around 20 related neurodegenerative diseases, called tauopathies. Currently, tau pathology is a major drug target for the treatment of AD and related tauopathies. Both active and passive tau immunization human clinical trials at various stages are underway. Initial results range from negative to partially promising. Future studies will reveal whether tau therapy alone or in combination with drugs targeting Aβ and/or neurodegeneration will be required to achieve the most effective treatment for AD and related disorders.

Keywords: Alzheimer's disease; amyloid beta pathology; neurodegeneration; tau pathology; tauopathies.

Figure 1.. Alzheimer’s disease (AD) pathology involves a vicious cycle of neurodegeneration, Aβ and hyperphosphorylated tau pathologies.

AD is a multifactorial disorder that appears to involve several different mechanisms. Independent of the etiology, whether familial or sporadic forms of the disease, it is characterized by brain neurodegeneration associated with Aβ and tau pathologies. Aβ immunotherapies have shown, at best, only a partial rescue of the disease. At present, it is not known whether inhibition of both tau and Aβ pathologies alone or also combined with inhibition of neurodegeneration will be required for the most effective treatment of AD. Our hypothesis is that highly effective inhibition and prevention of AD can be achieved by shifting the balance from neurodegeneration to neural regeneration and inhibition of associated tau and Aβ pathologies. Both physiological and reparative regeneration occurs throughout life in human brain to sustain tissue homeostasis and repair as well as synaptic renewal through synaptic turnover (Martino et al., 2011; Sudhof, 2021). AD brain responds to neurodegeneration by stimulating neural regeneration, but the diseased brain lacks sufficient appropriate neurotrophic activity, and hence this attempt fails (Li et al., 2008). Although studies have implicated both Aβ and tau pathologies in causing cognitive impairment, neurodegeneration is the most proximal pathology to the development of dementia in AD patients. Substantial evidence suggests that the Aβ and hyperphosphorylated tau (ptau) oligomers, rather than Aβ plaques and tau neurofibrillary tangles (NFTs), are the primary cause of neurodegeneration and dementia. Plaques and tangles are defence responses of the diseased brain whereby it forms, respectively polymers of Aβ and hyperphoshorylated tau, which are inert space occupying lesions; in the case of NFTs as intraneuronal lesions, they appear to eventually choke the cells to death. Development of compounds such as P021 that can shift the balance in the treatment of AD from neurodegeneration to neural regeneration and consequently inhibit both tau and Aβ pathologies represents a novel and promising therapeutic approach. A recent study showed the therapeutic benefit of inhibition of neurodegeneration by reduction of long non-coding RNA MEG3 in a human neuron xenograft mouse model of AD (Balusu et al., 2023).