# Small Molecule Mitochondria-Targeted Therapeutics for AD (Supplement)

> **NIH NIH UH3** · MAYO CLINIC ROCHESTER · 2022 · $284,436

## Abstract

Project Summary/Abstract (from the awarded grant application)
Abnormal energy homeostasis in Alzheimer’s Disease (AD) is associated with synaptic dysfunction and
neurodegeneration. Emerging data generated using multiple systems biology approaches and meta-analysis in
AD patients identified an AMP-protein kinase (AMPK) integrated signaling network that operates down stream
of mitochondrial energy production and could provide neuroprotection in AD. Partial inhibition of mitochondrial
complex I (MCI) improves glucose uptake and utilization, dendritic spine maturation, long-term potentiation,
synaptic activity, cognitive function, and reduces A and pTau accumulation, oxidative stress and inflammation
resulting in neuroprotection in pre- and symptomatic preclinical mouse models of AD and aging. These studies
suggest that novel strategies to alter mitochondrial energy homeostasis may have profound translational
therapeutic potential for AD. Using multiple biochemistry, computational and systems biology approaches, and
extensive in vivo translational studies, we developed small molecules that bind next to the flavin
mononucleotide redox center of MCI mildly inhibiting its activity. The molecular mechanism of MCI inhibitors
impinges on pathways induced by caloric restriction and exercise including activation of AMPK; increased
resistance to oxidative stress; enhanced mitochondrial biogenesis, energetics, dynamics and function;
reduction of glycogen synthase kinase 3 activity; increased levels of brain-derived neurotrophic factor (BDNF)
and synaptic proteins in vivo; a reduction in levels of A and pTau and inflammation ultimately blocking
neurodegeneration in AD mice. The team confirmed these effects in a range of systems (primary mouse
neurons, multiple mouse models of familial AD, wild-type mice fed with a high fat diet, chronologically aged
mice, mitochondria isolated from mouse and human brain, human lymphocytes, fibroblasts and neuronal cells
differentiated from human iPSCs), supporting the high translational potential of this approach. The advantages
of the molecules include the ability to penetrate the blood brain barrier, low toxicity, in vivo efficacy, and the
known molecular target. Based on the target validation and the identification of the molecular mechanism, we
developed multiple in vitro and in vivo assays that were used for structure-activity relationship (SAR) studies
resulting in the development of a robust Discovery Funnel and arrays of novel series of proprietary compounds
MCI inhibitors with promising drug-like properties (US patent granted). They propose to advance small
molecule therapeutics to the clinic by entering the BPN at the Discovery stage where, with the team of the BPN
Consultants and CROs, we will progress toward the identification of preclinical and development candidates,
and to the submission of the IND application in preparation for a Phase I Clinical Trial.

## Key facts

- **NIH application ID:** 10621603
- **Project number:** 3UH3NS113776-02S1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Eugenia Trushina
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $284,436
- **Award type:** 3
- **Project period:** 2022-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10621603

## Citation

> US National Institutes of Health, RePORTER application 10621603, Small Molecule Mitochondria-Targeted Therapeutics for AD (Supplement) (3UH3NS113776-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10621603. Licensed CC0.

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