The VGF (nonacronymic) gene encodes a neuronal and neuroendocrine protein precursor that is post-translationally processed with cell- and tissue-type specificity into multiple bioactive peptides. These peptides are secreted and are involved in numerous physio/pathological functions, including reproduction, depression, obesity, memory and also neurodegenerative diseases, in particular Alzheimer’s disease (AD). Recent studies conducted by the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) consortium have further identified reduced VGF levels in the brains of AD subjects that correlate with stage of disease. Druggability of the VGF pathway is of intense interest in many fields. We propose to use recombinant mouse models of AD and a humanized VGF receptor to determine the efficacy of human VGF and one of its neuroactive peptides, TLQP-21, in prevention and amelioration of the “AD phenotype” in these mice.