# Hippocampal circuit plasticity in human normal aging and Alzheimer's Disease

> **NIH NIH R56** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2020 · $759,703

## Abstract

In 2050, the population aged 65 and over will be almost double the number in 2012, increasing the importance
of late life cognitive health and resilience. Adult hippocampal neurogenesis (AHN) is crucial for memory functions
and recovery from stress in rodents. Little is known about human AHN in healthy aging and Alzheimer’s Disease
(AD), less is known about age and AD effects on synaptic plasticity and brain circuits. In aging rodents and non-
human primates, adult-generated neural cells tend to favor differentiation into glia instead of neurons, but
phylogenetic differences dictate human studies. AHN studies require rigorous methods for visualization of AHN
markers and data interpretation. These include assuring brain tissue quality, standardized tissue processing, use
of brain toxicology and neuropathology, and strict clinical inclusion/exclusion criteria based on adequate clinical
data. We and others have confirmed persistent AHN with aging in subjects without AD, but we found age-
associated declines in angiogenesis and neuroplasticity as defined by expression of polysialiated cell adhesion
molecule (PSA-NCAM) in fewer cells of the dentate gyrus (DG), which could reflect changes at the dendrite,
spine or synaptic level, because PSA-NCAM is expressed with dendrite remodeling, neuron migration, and long
term potentiation. Our preliminary data show that Kruppel Like Factor 9 (Klf9), a transcription factor necessary
for neurogenesis-dependent synaptic plasticity and neuronal differentiation, declines with normal aging in human
DG. We reported that the age-related angiogenesis decline is directly proportional to fewer cells expressing PSA-
NCAM. Angiogenesis and AHN are regulated by vascular endothelial growth factor receptor 2 (VEGFR2), and
we have pilot data showing fewer intra- and extra-vascular DG cells expressing VEGFR2 in older people. Studies
of AHN in AD have shown conflicting findings of increased, no change, and deficits of AHN correlating with
cognitive decline. We propose new techniques that have never been applied to study AHN, dendrite, spine,
synaptic and vascular plasticity in normal human aging or AD brain tissue. To understand what sustains AHN
and synaptogenesis, we will examine their relationship to expression of molecular regulators (Klf9 and VEGFR2).
The sample will include hippocampi from the Brain Banks of NIMH and the New York AD Research Center: 80
without neuropsychiatric illness, neuropathology or psychotropic drug use, age 14-90, and 20 with AD, age 65-
90. Aims: 1. To study the neuronal or glial phenotype of doublecortin (DCX)-positive cells and quantify AHN and
gliogenesis across the human lifespan. 2. To study age-associated changes in dendrite, spine and synapses
and their molecular regulator Klf9 in CA1, CA3 and DG: 2a. Golgi-stained dendrite and spines; 2b. Number and
length of neurofilament-immunoreactive dendrites; 2c. Pre/post-synaptic and dendritic protein expression:
SYN1, PSD95 and spinophilin; 2d. Klf9 mR...

## Key facts

- **NIH application ID:** 10231302
- **Project number:** 1R56AG063372-01A1
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Maura Boldrini Dupont
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $759,703
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231302

## Citation

> US National Institutes of Health, RePORTER application 10231302, Hippocampal circuit plasticity in human normal aging and Alzheimer's Disease (1R56AG063372-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10231302. Licensed CC0.

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