Neuroinflammation, a core pathological feature observed in several
neurodegenerative diseases, including
Alzheimer's disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the
disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological
amyloid-beta peptide (Aβ) plaques and aggregates of the
tau protein.
Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to
neuroinflammation. This intricate relationship between tau pathologies and
neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau's influence on
neuroinflammation presents a frontier for the development of innovative
immunotherapies.
Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using
immunotherapy targeting tau pathological
epitopes and structures with a wide array of
antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau
immunotherapies may include combining treatments with Aβ
immunotherapy, which may result in more significant clinical outcomes for
neurodegenerative diseases.