Antibody Therapeutics Targeting Aβ and Tau

Abstract

The astonishing findings that active and passive immunization against amyloid-β (Aβ) in mouse models of Alzheimer's disease (AD) dramatically decreased amyloid burden led to a rapid initiation of human clinical trials with much enthusiasm. However, methodological issues and adverse effects relating to these clinical trials arose, challenging the effectiveness and safety of these reagents. Efforts are now underway to develop safer immunotherapeutic approaches toward Aβ and the treatment of individuals at risk for AD before or in the earliest stages of cognitive decline with new hopes. Furthermore, several studies have shown tau as a potential immunotherapeutic target for the treatment of tauopathy-related diseases including frontotemporal lobar dementia (FTLD). Both active and passive immunization targeting tau in mouse models of tauopathy effectively decreased tau pathology while improving cognitive performance. These preclinical studies have highlighted tau as an alternative target with much anticipation of clinical trials to be undertaken.

Figure 1.

Schematic of potential mechanisms for antibody-mediated clearance of amyloid-β. Antibodies within the central nervous system (CNS) potentially clear amyloid deposits in a microglia-dependent phagocytosis mechanism (“CNS hypothesis”). Local clearance in the CNS may also occur in a non-Fcγ mediated mechanism. Alternatively, antibodies within the periphery sequester amyloid-β (Aβ), altering the dynamics of Aβ into the CNS and lowering amyloid burden (“peripheral sink hypothesis”). It is possible that more than one mechanism is important.

Figure 2.

Schematic depicting tau fibril propagation occurring via a non-cell-autonomous mechanism from unhealthy neurons to neighboring neurons. Immunotherapeutic targeting of tau species potentially blocks tau propagation and seeding.