UC San Diego

Alzheimer's disease (AD) is the most common neurodegenerative disorder and age-related dementia in the elderly. It affects 5.4 million people in the United States and it is the sixth-highest cause of death. Neuropathologically, AD is characterized by the accumulation of insoluble extracellular plaques composed of β-amyloid (Aβ) and intracellular tangles consisting of phosphorylated forms of the microtubule-associated protein, tau, in the brain. Current treatments only temporarily and mildly boost cognitive function and as such they are unable to slow or halt the underlying pathophysiological progression of the disease. Our group has previously shown that two small molecules, CRFR1 antagonist (R121919) and γ-secretase modulator (BPN-15606), were able to attenuate Aβ plaque load AD, in vivo and vitro, respectively. Here we extend the study by using a polytherapeutic approach. We tested R121919 and BPN-15606 alone as monotherapy and together as polytherapy in an Alzheimer’s disease transgenic mouse model. We hypothesized that polytherapeutic approaches that impact multiple pathways in the AD brain will be efficacious over monotherapy due to the complexity of pathways of neurodegeneration. Their effects alone and in combination was compared on relevant behavioral, pathological, and biochemical endpoints. Our results indicate that chronic administration of R121919, BPN-15606, or the polytherapy present to be safe in terms of liver function. AD mice treated with BPN-15606 or polytherapy significantly ameliorated Aβ, but also showed significant lack of weight gain. No treatment effect was seen in mice receiving R121919. As for the cognitive function, AD mice receiving any of the treatments did not show improvement in either the acquisition or spatial memory assessment. However, the combo-treated cohort was impaired in latency acquisition compared to vehicle suggesting adverse cognitive function. Our results suggest that the polytherapy was not efficacious over monotherapy, but BPN-15606 alone demonstrated to be a potential disease-modifying therapeutic approach with limited adverse effects and without liver toxicity