Turning the tide on Alzheimer’s disease: modulation of γ-secretase

Abstract

Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the “amyloid hypothesis,” which states that the accumulation of Aβ peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved aducanumab, the first Aβ-targeted therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-Secretase is an intramembrane aspartyl protease that is critical for the generation of Aβ peptides. Activity and specificity of γ-secretase are regulated by both obligatory subunits and modulatory proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-secretase has been a challenging drug target for AD. γ-secretase modulators, however, have dramatically shifted the approach to targeting γ-secretase. Here we review γ-secretase and small molecule modulators, from the initial characterization of a subset of NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-secretase, in which small molecule probes enabled structural and functional insights into γ-secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-secretase will be part of a new wave of AD therapeutics.

Amylin and Secretases in the Pathology and Treatment of Alzheimer’s Disease

“…Table 1 outlines the current status of clinical trials among these agents by targeting secretase and amylin [ 67 , 110 , 120 , 121 , 122 , 123 , 126 , 150 ]. Moreover, the findings of this review with regard to α-secretase activators, β-secretase inhibitors, γ-secretase inhibitors, and amylin agonists align with the findings of previous reviews but also build upon with recent evidence on small peptide therapeutics as well [ 27 , 72 , 149 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 ]. This is encouraging given the current development of newer of AD therapeutics outside of small peptides.…”

Biomarkers for the Diagnosis of Alzheimer’s Disease in Clinical Practice: The Role of CSF Biomarkers during the Evolution of Diagnostic Criteria

“…Furthermore, Aβ38 has an inhibitory effect on fibril formation, but the most significant effect was observed by the proportion of 1:3:2 or 1:4:1 of Aβ 1-40/Aβ38/Aβ37 [38]. This and other studies appear to indicate a therapeutic target related to γ-secretase modulators, which could reduce Aβ plaque formation [35,39,40]. There have been several promising attempts to use other conformations.…”

Alzheimer’s Disease-Related Genes Identified by Linking Spatial Patterns of Pathology and Gene Expression

“…Recent evidence has suggested that aberrant Notch signaling could result in the neurodegeneration seen in AD ( Woo et al, 2009 ; Kapoor and Nation, 2021 ). In addition, the failure of γ-secretase inhibitors as treatments of AD has been partly attributed to its deleterious effects on Notch signaling, which may have counteracted any benefits from reduced Aβ production ( Luo and Li, 2022 ). MGAT5 was implicated as part of Golgi metabolic pathways and has attracted recent interest due to its human-specific differential expression in brain tissue layers as well as in AD ( Jorge et al, 2021 ).…”