Project Summary Despite immense efforts, the mechanisms underlying Alzheimer?s disease (AD) are not well understood. Exploiting transgenic mouse models of AD as well as cell culture models, which we established in the current funding period, we now propose a collaborative effort built on two interrelated directions, each designed to uncover the molecular mechanisms allowing alpha-synuclein to influence AD pathology and AD-associated synaptic and cognitive deficits. We will first test whether temporal regulation of SNCA, the gene encoding alpha- synuclein (?Syn), in adult mice attenuates central components of the phenotype of AD mouse models. We will test the hypotheses that ?Syn stalls the conversion of prefibrillar amyloid-? (A?) assemblies into fibrils thereby exacerbating synaptic injury. If successful, these studies will define the role of ?Syn as an important modulator of AD pathology and AD-associated deficits and will establish a proof-of-principle to support testing therapeutic strategies that target ?Syn in the context of AD.