There is much data that continue to point to accumulation of amyloid beta as a contributor to the pathogenesis of Alzheimer’s disease—particularly in early-onset versions of the disease. In Down syndrome, for example, a triplication of the number of inherited copies of chromosome 21 increases the gene dosage of the amyloid precursor protein that is localized to that chromosome. As a result, patients with Down syndrome develop the neuropathology associated with Alzheimer’s disease, plaques and tangles, at an accelerated rate. This research product aims to mitigate neurodegeneration in Down syndrome patients with Alzheimer’s disease (AD-DS) as well as in other types of Alzheimer’s disease using small molecules called gamma secretase modulators. The researchers have found that GSMs can reduce the levels of the toxic products of APP. This project will validate the effects of a GSM, UCSD776890, in a mouse model of AD-DS to determine whether AD-related neurodegeneration and pathology can be ameliorated. UCSD776890 has excellent pharmacological characteristics and is poised to be effective in clinical trials. This research will provide insights into the efficacy of this GSM in order to support its filing as an investigational new drug, as well as the design of future clinical trials for AD-DS.
The products of the amyloid precursor protein (APP) play a defining role in Alzheimer’s disease (AD) in people with Down syndrome (AD-DS), as well as in other types of AD. We aim to mitigate neurodegeneration in AD-DS using small molecules called gamma-secretase modulators (GSMs). We have found that GSMs reduced the levels of the toxic products of APP. Here, we propose to validate the effects of a GSM, UCSD776890, in a mouse model of AD-DS to ask whether or not we can prevent and/or rescue neurodegeneration and AD-related pathologies. UCSD776890 has excellent pharmacological characteristics and is well-suited for clinical trials. Our findings will provide valuable insights into the efficacy of this GSM and, in so doing, support an IND filing and inform the design of future trials for AD-DS.