Beyond amyloid: nanobody-mediated neuroinflammatory therapy for Alzheimer's disease

Alzheimer's disease (AD) is one of the most common and devastating neurodegenerative diseases, characterized by accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles of tau protein, and persistence of neuroinflammation, leading to progressive cognitive decline, loss of independence, emotional and financial strain on families, and significant societal costs. Current anti-amyloid treatments are partly successful in removing Aβ amyloid, but often lead to increased inflammation. This leads to limited therapeutic efficacy and causes side effects such as amyloid-related imaging abnormalities. In addition, they do not address neuroinflammation in AD patients. In this review, we discuss a new therapeutic strategy that combines single-domain antibodies (sdAbs, nanobodies) against Aβ fibrils and anti-inflammatory drugs and applies them to the regions of neuroinflammation associated with the plaques in AD patients. This strategy aims to control the function of activated microglia and astrocytes, thereby avoiding unnecessary immunosuppression. We also discuss the unique features of sdAbs, including small size, good tissue penetration, and lack of Fc-mediated immune reactions, as well as relevant payloads (i.e., small molecules, biologics, and nanoparticles) and delivery systems. This immunomodulatory therapy targets the plaques specifically and therefore represents a promising opportunity to improve amyloid clearance and target the inflammatory components of AD, potentially improving the therapeutic efficacy of the disease.