The Immune System as a Therapeutic Target for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and is the most common cause of dementia. Furthermore, aging is considered the most critical risk factor for AD. However, despite the vast amount of research and resources allocated to the understanding and development of AD treatments, setbacks have been more prominent than successes. Recent studies have shown that there is an intricate connection between the immune and central nervous systems, which can be imbalanced and thereby mediate neuroinflammation and AD. Thus, this review examines this connection and how it can be altered with AD. Recent developments in active and passive immunotherapy for AD are also discussed as well as suggestions for improving these therapies moving forward.

Keywords: Alzheimer’s disease; aging; immunotherapy; microglia; peripheral immune system.

Figure 1

APP amyloidogenic and non-amyloidogenic processing pathways. In the nonamyloidogenic pathway, APP is cleaved by α-secretase to produce a soluble amino-terminal of the amyloid precursor protein, as well as a C-terminal fragment (C83) that can subsequently be cleaved by γ-secretase to produce the p3 extracellular fragment and amyloid precursor protein intracellular domain (AICD). In the amyloidogenic pathway, β-secretase cleaves APP to generate the soluble amyloid precursor protein β- and a C-terminal fragment (C99). Then, the cleavage of C99 by γ-secretase leads to the release of amyloid-β and AICD.

Figure 2

Possible mechanisms of anti-Aβ antibodies. Passive immunotherapies directly supply antibodies to the host and anti-Aβ antibodies interfere with the β-amyloid cascade at various levels. (A) Blocking of oligomer formation. (B) Plaque phagocytosis by microglia (Fc-mediated phagocytosis). (C) Direct mechanism of action towards Aβ plaques via antibody-mediated disassembly. (D) Slowing and halting of fibril elongation. (E) The refuted peripheral sink mechanism (monomer efflux from CNS) and shift in concentration gradient.