Current and Emerging Pharmacological Targets for the Treatment of Alzheimer's Disease.

Abstract

No cure or disease-modifying therapy for Alzheimer's disease (AD) has yet been realized. However, a multitude of pharmacological targets have been identified for possible engagement to enable drug discovery efforts for AD. Herein, we review these targets comprised around three main therapeutic strategies. First is an approach that targets the main pathological hallmarks of AD: amyloid-β (Aβ) oligomers and hyperphosphorylated tau tangles which primarily focuses on reducing formation and aggregation, and/or inducing their clearance. Second is a strategy that modulates neurotransmitter signaling. Comprising this strategy are the cholinesterase inhibitors and N-methyl-D-aspartate receptor blockade treatments that are clinically approved for the symptomatic treatment of AD. Additional targets that aim to stabilize neuron signaling through modulation of neurotransmitters and their receptors are also discussed. Finally, the third approach comprises a collection of 'sensitive targets' that indirectly influence Aβ or tau accumulation. These targets are proteins that upon Aβ accumulation in the brain or direct Aβ-target interaction, a modification in the target's function is induced. The process occurs early in disease progression, ultimately causing neuronal dysfunction. This strategy aims to restore normal target function to alleviate Aβ-induced toxicity in neurons. Overall, we generally limit our analysis to targets that have emerged in the last decade and targets that have been validated using small molecules in in vitro and/or in vivo models. This review is not an exhaustive list of all possible targets for AD but serves to highlight the most promising and critical targets suitable for small molecule drug intervention.