The endopeptidase delta-secretase is partly responsible for mediating the accumulation of beta-amyloid plaques and tau protein aggregates: two prime suspects in the pathogenesis of Alzheimer’s disease. A new study reports an orally bioactive and highly selective small molecule inhibitor of delta-secretase that can prevent the accumulation of aggregated proteins and improve cognition in mouse models of Alzheimer’s disease.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and a decline in cognitive abilities. Beta-amyloid plaques (consisting of insoluble deposits of beta-amyloid peptide) and neurofibrillary tangles (composed of aggregates of protein tau) are commonly observed in the brain of AD patients, and are believed to be causative in its pathogenesis. Currently, no cure exists for the disease and massive research efforts are underway in finding interventions that can halt the progression of AD by preventing the accumulation of these proteins.
Delta-secretase is an endopeptidase that cleaves both amyloid precursor protein (APP) and tau, subsequently leading to their aggregation and accumulation. So far, most efforts at identifying/designing inhibitors of delta-secretase have focused on small peptides. Although specific in action, peptides undergo proteolytic degradation once in the body, and therefore have poor bioavailability profiles. A new study published in Nature Communications by researchers at Emory University and scientists in China and Austria, reported on a novel and specific small molecule inhibitor of delta-secretase.
The authors performed high throughput screening of a 54,384 compound chemical library, and came up with several lead molecules showing inhibitory action on delta-secretase. Further screening on the basis of ability to cross the blood-brain barrier resulted in a single hit: compound 11. In vitro studies indicated that it was non-toxic, non-carcinogenic and highly specific to delta-secretase. In vivo studies revealed bioavailability of almost 70%.
Chronic oral administration of compound 11 to P301S transgenic mice (which expressed an aggregate-prone form of tau) inhibited delta-secretase activity, decreased the accumulation of tau, halted the decline in cognitive abilities, and increased the density of neuronal synapses and synaptic plasticity in the brain. Treatment with compound 11 also decreased the accumulation of beta-amyloid plaques in the brains of yet another transgenic mouse with rapid-onset beta-amyloid pathology. Indices of spatial learning and memory in these AD mice improved after treatment with compound 11.
Overall, the study identified a potent, non-toxic and highly specific inhibitor of delta-secretase that has a protective effect in mouse models of AD. The authors propose further clinical development and evaluation of the compound as a therapeutic intervention for the treatment of AD.
Written By: Debapriya Dutta, PhD