A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies

Abstract

Introduction: Primary tauopathies are neurological disorders in which tau protein deposition is the predominant pathological feature. Alzheimer's disease is a secondary tauopathy with tau forming hyperphosphorylated insoluble aggregates. Tau pathology can propagate from region to region in the brain, while alterations in tau processing may impair tau physiological functions. Methods:We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. Results:The past 15 years have seen >30 drugs interfering with tau aggregation, processing, and accumulation reaching the clinic. Initial results with tau aggregation inhibitors and anti-tau monoclonal antibodies have not shown clinical efficacy. Discussion:The reasons for these clinical failures are unclear but could be linked to the clearing of physiological forms of tau by non-specific drugs. Research is now concentrating efforts on developing reliable translational animal models and selective compounds targeting specific tau epitopes, neurotoxic tau aggregates, and posttranslational tau modifications.

The effects of active rehabilitation on symptoms associated with tau pathology: An umbrella review. Implications for chronic traumatic encephalopathy symptom management

“…While the mechanisms and areas affected may differ between tauopathies, the progressive neural degeneration and associated clinical symptoms are attributed to synaptic dysfunction and impairments to neural connectivity which accumulated p-tau creates. With no intervention, the process leads to neural cell death and subsequent atrophy of affected regions [ 3 , 4 ]. Exercise can promote neurogenesis and improve cerebral blood flow [ 18 – 20 ].…”

“…Tau stabilizes those microtubules which provide shape and structure to neural axons, dendrites and synapses. Tau has also been found to aid in axonal transport, synaptic transmission, cytoskeletal regulation and proteostasis [ 2 – 4 ]. Tau has a reversible hyperphosphorylation capability which provides neural protection and regulation.…”

“…Tau has a reversible hyperphosphorylation capability which provides neural protection and regulation. Subsequently, the development of pathogenic tau formulation has been associated with irreversible hyperphosphorylation and the disruption of microtubule stability [ 4 ]. It remains unclear what order this occurs in or what the specific pathophysiology is [ 4 ], but the release of tau and translocation to synapses may lead to further spread of pathogenic tau [ 1 , 2 ].…”

“…Subsequently, the development of pathogenic tau formulation has been associated with irreversible hyperphosphorylation and the disruption of microtubule stability [ 4 ]. It remains unclear what order this occurs in or what the specific pathophysiology is [ 4 ], but the release of tau and translocation to synapses may lead to further spread of pathogenic tau [ 1 , 2 ]. Accumulation of pathogenic tau can disrupt neural connectivity and synaptic function, eventually leading to neural cell death and atrophy of several brain regions characteristic of diseases such as Alzheimer’s disease (AD), Corticobasal degeneration (CBD), Frontotemporal degeneration/dementia (FTD), Lewy Body disease (LBD) and Parkinson’s disease (PD).…”

“…Factors such as genetics or metabolic syndromes can trigger a pathogenic tau formation. Exposure to brain injury has also been found to result in neurodegenerative tauopathy, termed Chronic Traumatic Encephalopathy (CTE) [ 1 , 3 , 4 ].…”