Novel directions for investigating the role of VGF in comorbid Major Depressive Disorder and Alzheimer's disease

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

Late onset Alzheimer’s disease (LOAD), the most common form of dementia, and Major Depressive Disorder (MDD) frequently co-exist, but the co-morbidity is not explained by common genetic variants. We have therefore sought to identify shared pathophysiological mechanisms, and VGF is implicated in both AD and MDD. Several AMP-AD groups exhaustively profiled gene expression in brain regions from multiple cohorts of AD and control subjects, and then performed systems biology analyses which collectively identified VGF (acronymic) and its network as a key driver (regulator) implicated in LOAD. Additional evidence supporting the relevance of VGF to AD includes: 1) identification of reduced VGF levels in the brains and CSF of patients with neurodegenerative disease including AD; 2) progressive decrease of VGF CSF levels with AD progression, suggesting its use as a biomarker; 3) protective effect against the LOAD risk of an ApoE4 haplotype by high levels of VGF; and 4) our data showing that hippocampal and cortical VGF levels are reduced in subjects with MDD, in mouse models of depression-like behavior, and in the 5xFAD mouse AD model. Our preclinical studies show that 1) VGF overexpression in 5xFAD hippocampus reduces cortical and hippocampal amyloid deposition, microgliosis, astrogliosis, and cognitive impairment, and rescues neurogenesis deficits, and 2) chronic icv infusion of the VGF- derived neuropeptides TLQP-21 or TLQP-62 (named by the N-terminal 4 amino acids and length) have similar effects. As not all VGF activities are easily explained by its known receptors, we therefore identified additional receptors and active members of the VGF network. Screening of a proprietary expression library identified TLQP- 21 binding to the neuropilins, NRP1 and NRP2, and TLQP-62 binding to the fibroblast growth factor receptor 2 (FGFR2). In Aim 1, we propose to better characterize these novel binding interactions biochemically and computationally, and to determine their functional role(s) and downstream signaling, in vivo, in the APP/PS1 AD mouse model, including in depression-like behavior. In vitro, we will assess their effects on microglial migration, activation, and amyloid uptake. In Aim 2, to better understand VGF actions that may be transduced via its causal network, which we constructed from AD and control subjects with and without MDD, we will investigate the role in AD pathogenesis of the RAB3A interactor called rabphilin 3A (RPH3A), a key node in the VGF protein network and regulator of neurotransmitter release and synaptic plasticity. VGF and RPH3A also share an association with cognitive resilience in aged populations. We will assess the outcomes of RPH3A overexpression or ablation on neuropathology, synaptic function, transcriptomics, and AD- and MDD-related behavioral phenotypes in the APP/PS1 and the humanized hAbetaKI (LOAD) mouse models, to determine similarities and differences between this nodal gene and VGF. In Aim 3, we will explore novel subnetworks and key drivers, comparing expression in AD and AD+MDD brain, and cross-cell-type interaction networks that regulate neuron-microglial VGF crosstalk. Our studies will elucidate new mechanisms and targets underlying comorbid AD and MDD.