Therapeutic Strategies Targeting Amyloid-β in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-beta (A beta) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. A beta is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by beta- and gamma-secretases while APP proteolysis by alpha-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, A beta dyshomeostasis results in the accumulation and aggregation of A beta into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. A beta-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on A beta-protein targeted AD drugs, including beta-secretase inhibitors, gamma-secretase inhibitors and modulators, alpha-secretase activators, direct inhibitors of A beta aggregation and immunotherapy targeting A beta, focusing mainly on those currently under clinical trials.