Modeling Late-Onset Alzheimer's Disease in Mice

Abstract

As part of our participation in the Model-AD consortium, the UCI group has developed at least 12 novel mouse models that are relevant to studying the mechanisms underlying late-onset Alzheimer's disease (LOAD). These new models include variants in Abca7, Clu, Picalm, and Trem2. Modeling LOAD is hampered by the subtle effects imparted by the GWAS variants versus the much stronger phenotypic effects imparted by autosomal dominant AD mutations. We have successfully built a platform mouse in which the Aβ sequence has been humanized, and we found that wildtype-hAβ is sufficient to induce synaptic deficits and loss and accelerate the formation of astrocyte-associated Periodic Acid Schiff granules, normally associated with aging. We are actively introducing human tau alleles into these platform mice. Our strategy is to couple the humanizing of critical AD genes (APP, tau) with GWAS variants (Abca7, Clu, Picalm,) to better assess the impact that these alleles have on the phenotype. Modeling late-onset Alzheimer's disease represents a significant challenge, but success will likely yield substantial insights into disease mechanisms and advance drug discovery and evaluation efforts.