VGF, a Novel Therapeutic Effector of Alzheimer’s Disease Pathogenesis and Progression

2017

Alzheimer’s disease is the most common form of dementia and is characterized by a progressive decline in cognitive function. Neurotrophic growth factors, including brain-derived neurotrophic factor(BDNF), are well-known modulators of synaptic plasticity and neuroprotection and have been a major research interest in age- and disease-related cognitive dysfunction. VGF (nonacronymic), a secreted neuronal and endocrine protein whose expression is induced by BDNF, is processed into several bioactive peptides that function in memory formation and neuroprotection. Biomarker studies have identified decreased levels of VGF-derived peptides in the cerebrospinal fluid of AD patients, and large-scale genomics studies by the Accelerating Medicines Partnership-Alzheimer’sDisease consortium have recently converged on VGFas a critical regulator in the signaling networks that underlie AD pathogenesis and progression in human patients. Recent data collected in our labs further demonstrate that VGF overexpression or administration of VGF-derived peptides to the 5XFAD mouse model of AD reduce amyloid plaque load, microgliosis, and astrogliosis in the brain, in a region-specific manner.

We propose to investigate how the VGF-derived peptide TLQP-21 delays or reverses neuropathology in the 5xFADbrain by studying its interaction with the complement C3a receptor (C3aR1) on cultured microglia, its regulation of microglial amyloid uptake and gene expression, and potential modulation of VGF actions by beta-adrenergic receptor (AR) signaling, which reportedly increases beta-amyloid phagocytosis and generally reduces amyloid load in AD models (although this is controversial). In addition, we will determine the underlying pathways by which VGF or VGF-derived peptide TLQP-21 blocks or delays development of neuropathology and impacts microglial function in mouse tauopathy (PS19) and amyloid (5XFAD)models, utilizing large-scale genetics approaches to analyze gene expression and to construct signaling networks. The proposed experiments will validate a novel AD target and will test new approaches to reduce neuroinflammation in neurodegenerative disease.