The pathological cognitive decline of Alzheimer's Disease (AD) features decreased synaptic plasticity, lowered brain activity, and accelerated neuronal loss usually initiated within the medial temporal lobe area. A major research goal has therefore been to identify therapeutic avenues that modify disease progression. Neurotrophic growth factors, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), are well known modulators of synaptic plasticity, neurogenesis, and neuroprotection, and have been a major research interest in age- and disease-related cognitive dysfunction. VGF (non-acronymic), a secreted neuronal and endocrine protein whose expression is induced by NGF and BDNF, is processed into several bioactive peptides that function in memory formation, neuroprotection, and energy homeostasis. Previous work from our lab and others has demonstrated a significant decline in VGF expression in the brains of patients with neurodegenerative disease, including AD and amyotrophic lateral sclerosis (ALS). Moreover, a number of biomarker studies have identified VGF-derived peptides in the CSF that are decreased in AD patients but not in control patients. These data indicate that decreased VGF expression in brain and CSF is associated with neurodegenerative disease; we propose to investigate whether this decline is mechanistically involved in disease pathogenesis or progression. In preclinical studies, we will investigate whether increased VGF expression resulting from gene therapy approaches, or intranasal administration of a VGF peptide that improves memory, delays or reverses memory dysfunction and neuropathology in a mouse model of AD. Our experiments will help test whether VGF-derived peptides could be therapeutically harnessed to suppress memory impairment in AD patients.