Redefining the battle against Alzheimer's with tau-focused treatments

By Neha MathurOct 29 2023Reviewed by Benedette Cuffari, M.Sc. In a recent article published in the journal Nature Reviews Neurology, researchers discuss the efficacy of tau-targeting Alzheimer's disease therapies and strategies that can be implemented to improve these treatments, especially immunotherapies.

There are two cardinal hallmarks of AD pathology, including the accumulation of amyloid-β , which is the primary component of extracellular plaques, and tau protein, the main constituent of neurofibrillary tangles . Previous attempts to develop AD-modifying therapeutics focused on Aβ pathology; however, most immunotherapies and secretase modifiers targeting Aβ, except for lecanemab and donanemab, either lacked efficacy or led to adverse effects.

Tau phosphorylation In addition to the reduced activity of protein phosphatase 2A , tau kinases are believed to contribute to tau hyperphosphorylation observed in AD. These enzymes can be indirectly or directly activated by Aβ, which can subsequently contribute to increased phosphorylation of tau and its misfolding.

Tau acetylation Tau acetylation has also been observed in AD and can lead to reduced solubility and degradation of tau protein. Salsalate, which is a small-molecule non-steroidal anti-inflammatory drug , has been shown to inhibit tau acetylation in preclinical mouse studies; however, this agent was not found to be successful in a phase I clinical trial.

Active tau immunotherapies Both active and passive immunotherapies have been developed to target tau proteins. Active immunotherapy delivers a tau immunogen and is associated with several advantages, including low costs, a polyclonal antibody response, and long-term efficacy. However, the endogenous roles of tau protein outside of its contribution to AD can lead to adverse autoimmune responses, which have been observed in preclinical mouse studies.

Passive tau immunotherapies Passive immunotherapy involves targeting specific tau epitopes that are involved in AD. An additional advantage of this approach is that any adverse effects can be mitigated through subsequent antibody clearance. Nevertheless, passive immunotherapy is often more expensive and must be administered more frequently, thus increasing the risk of secondary infection and other adverse effects.

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