# Caveolin-mediated neuronal signaling in differentiated adult human neuronal stem cells and the aging brain

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2020 · —

## Abstract

The population over 65 will increase to ~87 million by 2050. [Age alone is the greatest risk factor for
developing Alzheimer's disease (AD) and other forms of neurodegeneration such as Parkinson's disease (PD),
amyotrophic lateral sclerosis (ALS) or depression.] With no prevention or treatment, aged-related
neurodegeneration could reach 11-16 million by 2050. In 2035, today's Veterans will be middle-aged, with
health issues like those seen in aging Vietnam Veterans, complicated by comorbidities of posttraumatic stress
disorder, traumatic brain injury, and polytrauma. During neurodegeneration, the brain demonstrates region-
specific alterations in neuronal morphology, reduced structural plasticity and dendritic branching, and a
decreased capacity to regenerate. Brain function is underpinned by both electrical activity and chemical
communication between neurons; this communication between cells is necessary for re-establishing normal
brain function in the AD brain. In addition to genetic modulation that initiate neuronal growth, other
interventions such as 1) selective serotonin and dopamine reuptake inhibition (SDRI) to promote cAMP, or 2)
[neurotrophin receptor agonism] may promote structural and functional plasticity and improve behavior in
individuals afflicted with AD. Proper neuronal growth and guidance is dependent upon communication from
extracellular signals (i.e., spatial information) through the plasma membrane. A key plasmalemmal `hub' that
transduces the extracellular cues to the underlying cytoskeletal machinery are membrane/lipid rafts (MLR),
discrete microdomains enriched in sphingolipids, cholesterol, and scaffolding protein caveolin-1 (Cav-1).
Neuronal polarization and motility is dependent upon MLR localized in its leading edge. We have previously
demonstrated that neuron-targeted Cav-1 over-expression (achieved by linking it to a neuron-specific
synapsin promoter [SynCav1]): 1) enhances membrane cholesterol, MLR formation, and synaptic receptor
expression and signaling (TrkB); 2) increases serotonin receptor (5-HT6) and dopamine receptor-mediated
(D1R) cAMP formation; 3) promotes dendritic sprouting and arborization even in the presence of growth
inhibitors. A recent seminal publication from our group demonstrates that direct delivery of SynCav1 into the
brain augments structural and functional hippocampal neuroplasticity in adult mice (6 mo) and aged mice (20
mo) and improves hippocampal-dependent contextual fear learning and memory in both adult and aged mice.
These results provide proof-of-concept evidence that by increasing expression of Cav-1 specifically in neurons,
one can improve structural and functional neuroplasticity with positive behavioral outcome. This application
seeks to determine whether SynCav1 can induce similar neuroplastic changes in differentiated human
neuronal stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) and then to use SynCav1 in
combination with SSRIs, SDRIs, or TrkB agonism to...

## Key facts

- **NIH application ID:** 9898275
- **Project number:** 5I01BX003671-04
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** BRIAN P HEAD
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898275

## Citation

> US National Institutes of Health, RePORTER application 9898275, Caveolin-mediated neuronal signaling in differentiated adult human neuronal stem cells and the aging brain (5I01BX003671-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9898275. Licensed CC0.

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