100 years and counting: prospects for defeating Alzheimer's disease

Abstract

This week marks a century since the first description of Alzheimer's disease (AD). Despite approval of several drugs for AD, the disease continues to rob millions of their memories and their lives. Fortunately, many new therapies directly targeting the mechanisms underlying AD are now in the pipeline. Among the investigative AD therapies in clinical trials are several strategies to block pathogenic amyloid-beta peptides and to rescue vulnerable neurons from degeneration. Complementary but less mature strategies aim to prevent the copathogenic effects of apolipoprotein E and the microtubule-associated protein tau. New insights into selective neuronal vulnerability and the link between aging and AD may provide additional entry points for therapeutic interventions. The predicted increase in AD cases over the next few decades makes the development of better treatments a matter of utmost importance and urgency.

Fig. 1

Molecular and cellular processes presumed to participate in AD pathogenesis. Aβ peptides produced by neurons and other brain cells aggregate into a variety of assemblies, some of which impair synapses and neuronal dendrites, either directly or through the engagement of glial loops. Build-up of pathogenic Aβ assemblies could result from increased production or aggregation or from deficient clearance mechanisms. ApoE4 and tau promote Aβ-induced neuronal injury and also have independent adverse effects. Microglia could be beneficial or harmful, depending on which of their signaling cascades and functions are engaged. This multifactorial scenario leads to progressive disintegration of neural circuits, isolation and loss of neurons, network failure, and neurological decline.

Fig. 2

Drug targets involved in Aβ production and assembly. Aβ production depends on sequential proteolytic cleavage of APP by β-secretase (marked 1), also known as β-site APP-cleaving enzyme 1 (BACE1), and the multiprotein γ-secretase complex (2) (88). γ-Secretase targets include the enzyme’s active site, substrate docking site, and ATP-binding site (2a to 2c) and its predilection for γ-versus ε-cleavage (2d) or for generating Aβ₄₂ versus Aβ₄₀ (2e). The pathogenicity of released Aβ peptides depends on self-assembly (3). APP cleavage by α-secretases (ADAM family metalloproteases) prevents Aβ production (4). Caspase cleavage of the APP intra-cellular domain (AICD) generates a C31 fragment (5) that may participate in Aβ-induced toxicity or act independently.