# Physical exercise and Blood-brain communication: exosomes, Klotho and choroid plexus

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $768,387

## Abstract

Aging is the major risk factor for Alzheimer’s disease (AD). Numerous studies have confirmed that physical exercise
has positive effects in patients with AD and other neurodegenerative disorders. The majority of the studies examining
the effect of physical exercise in animal models of neurodegeneration have reported neuroprotection, improved
memory and cognitive performance. The molecular mechanisms of the interactions between the non-neuronal
systems involved in the physical/aerobic exercise and brain, however, remain poorly understood. The
antiaging protein, α-Klotho, has well-known neuroprotective activity, and recent studies demonstrated that systemic
elevation of α-Klotho protein in transgenic mice or injection of soluble α-Klotho fragment, enhanced cognition and
neural resilience in young, aging, and a murine disease model. Recent reports have suggested that α-Klotho levels
decline in brain of animal models of AD. It has been recently shown that physical aerobic exercise increases the
circulating levels of α-Klotho, and we have found that direct muscle contraction via neuromuscular electrical
stimulation significantly enhanced α-Klotho expression in the hippocampus. These findings raised the novel
hypothesis that skeletal muscle may be a regulator of circulating α-Klotho. We posit that muscle-induced stimulation
of α-Klotho may play a role in the beneficial effect of exercise on cognitive outcomes. Importantly, it has been
established that signals from periphery to the CNS are transmitted through mechanisms highly specific to choroid
plexus (CP) epithelium, and physical exercise increases the release and amount of extracellular vesicles into the
circulation. Our preliminary data demonstrate that α-Klotho is detectable at high levels in exosomes isolated from
plasma, and that muscle contractile activity increases the release and amount of α-Klotho-containing exosomes in
circulation. We also show that the exosomal cargo can transmit a signal to cells in vitro, thus affecting the expression
level of intracellular proteins. We hypothesize that the effects of physical exercise on CNS are results of signals
generated in peripheral muscles and transmitted to the brain via the CP epithelium. The signals are associated
with and depend on increased circulating levels of anti-aging protein,α-Klotho, released by muscles within
exosomes. This interdisciplinary research will integrate the expertise of AD researchers experienced with AD animal
models, analysis of AD-like pathology and omix approaches (R. Koldamova & I. Lefterov), established researchers
in biology of α-Klotho, rehabilitation, and aging (F. Ambrosio) and cell biology (C. St Croix). The goal of this proposal
is to further our understanding of the interactions between α-Klotho expression in skeletal muscles, physical activity
and brain, and to elucidate the relationship of age-related changes in skeletal muscle and progression of AD. Aim 1:
To determine if the effects of physical exercise on...

## Key facts

- **NIH application ID:** 10347309
- **Project number:** 5R01AG066198-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Fabrisia Ambrosio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $768,387
- **Award type:** 5
- **Project period:** 2020-01-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347309

## Citation

> US National Institutes of Health, RePORTER application 10347309, Physical exercise and Blood-brain communication: exosomes, Klotho and choroid plexus (5R01AG066198-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10347309. Licensed CC0.

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