# Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $282,334

## Abstract

Late onset Alzheimer's disease (LOAD) is the most common form of dementia, and is characterized by initial
memory loss and then a progressive decline in cognitive function. Members of the Accelerating Medicines
Partnership-Alzheimer's Disease (AMP-AD) program have exhaustively profiled gene expression in multiple
brain regions from multiple cohorts of AD and control subjects, and have then performed systems biology
analyses to identify molecular networks and drivers implicated in LOAD. VGF (non-acronymic) is one of the
top ranked AD drivers identified by several groups. Moreover, biomarker studies have consistently identified
reduced VGF levels in the brains and CSF of patients with neurodegenerative disease including AD, and show
that VGF is also a strong candidate biomarker of AD progression, with a 10% decrease in CSF levels of VGF
per year in diseased patients but not controls. We have shown that VGF overexpression in hippocampus
reduces cortical and hippocampal amyloid deposition, microgliosis, astrogliosis, and cognitive impairment, and
rescues neurogenesis deficits, in the 5xFAD mouse amyloidosis model, while chronic intracerebroventricular
(icv) infusion of the VGF-derived neuropeptides TLQP-21 or TLQP-62 (named by its N-terminal 4 amino acids
and length) has similar effects (El Gaamouch et al., Mol Neurodegener 2020; Beckmann et al., Nat Commun,
in press). TLQP-21 activates the complement C3aR1 G-protein coupled receptor (GPCR), a regulator of AD
pathogenesis that is expressed in the CNS on neurons, microglia, and astrocytes. The mechanism(s) of action
of TLQP-21 to modulate AD neuropathology will be further investigated in this administrative supplement
utilizing a novel LOAD mouse model developed by the Model Organism Development and Evaluation of Late-
Onset AD (MODEL-AD) consortium. This humanized Abeta knockin line (hAbeta-KI) expresses mouse beta
amyloid that contains 3 amino acid substitutions, which are found in human amyloid (G5R, F10Y, R13H), in
Abeta40 and Abeta42, and result in the formation of insoluble Abeta aggregates. Unlike the transgenic 5xFAD
model of familial early onset AD, that expresses human APP and presenilin with 5 familial mutations, and
develops a rapid, robust amyloidopathy, homozygous hAbetaKI mice do not overexpress APP, and slowly
develop neuropathology, detectable at 18 months of age, including significantly increased insoluble Abeta40
and 42, reduced soluble Abeta, increased hippocampal amyloid load, and impaired LTP. One specific aim is
proposed in this supplement, which will critically extend the parent project's investigation to a LOAD model.
This aim proposes (1) to study the underlying pathways by which VGF modulates progression of
neuropathology in the hAbeta-KI model, (2) to develop cohorts for long-term analysis, and (3) to determine
whether VGF actions require TLQP-21/C3aR1 signaling. Integrative approaches will be used to determine how
altered VGF or TLQP-21 levels impact microglial and neurona...

## Key facts

- **NIH application ID:** 10214197
- **Project number:** 3R01AG062355-03S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** MICHELLE E EHRLICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $282,334
- **Award type:** 3
- **Project period:** 2018-09-30 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214197

## Citation

> US National Institutes of Health, RePORTER application 10214197, Systems modeling of shared and distinct molecular mechanisms underlying comorbid Major Depressive Disorder and Alzheimer's disease (3R01AG062355-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10214197. Licensed CC0.

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