# Novel Cytoskeletal Stabilizers as Potential Treatments for Limbic Lewy Body Disorders

> **NIH NIH R21** · DUQUESNE UNIVERSITY · 2020 · $379,500

## Abstract

Abstract
Lewy body disorders are a family of fatal neurodegenerative conditions with α-synucleinopathic inclusions spreading
across brain regions involved in smell, affect, movement, and cognition. There are ~1.3M patients living in the US with
dementia with Lewy bodies (DLB) and another ~4M patients living with Parkinson's disease (PD). In addition, an
estimated ~50% of Alzheimer's disease patients display coexisting Lewy pathology (ADLB). If therapies could be
developed that slow the onset and spread of α-synucleinopathy, neurodegeneration might be mitigated and deterioration
of function would be delayed in millions of patients. Recent studies reveal that α-synuclein is a novel microtubule (MT)
dynamase, disrupting axonal transport across microtubules (MTs) in its aggregated form. Thus, tipping MT dynamicity
towards stabilization has emerged as a potential new treatment for neurodegenerative disorders. Accordingly, we
observed significant loss of detyrosinated (stable) α-tubulin in the olfactory bulb of men with Lewy body disorders. The
olfactory bulb/anterior olfactory nucleus (OB/AON) complex is closely connected with the limbic system and is one of
the earliest regions to display α-synucleinopathic inclusions in this family of conditions. We have also recently discovered
that two novel MT stabilizers (AG161-41 & 47) reduce the emergence of α-synuclein aggregates (up to a remarkable 48%)
in primary hippocampal cultures exposed to preformed α-synuclein fibrils. To our knowledge, this observation is unique,
as other MT stabilizers have not been demonstrated to mitigate Lewy pathology. Our human tissue and primary culture
pilot data make a compelling argument for further proof-of-concept studies. Thus, we will synthesize improved analogs
and test the hypothesis that MT stabilization tempers the pathological sequelae of exposure to α-synuclein fibrils in
cellular and animal models of limbic Lewy pathology. In Aim 1, we will synthesize additional AG161-41 & 47 and 12
novel analogs of AG161-47. In Aims 2A-C, we will determine if tipping the balance towards MT stabilization with these
14 compounds reduces inclusion density, cell loss, protein aggregation, and markers of MT destabilization in primary
limbic neuron cultures treated with α-synuclein fibrils. In Aim 2D, we will evaluate the compounds in assays of tubulin
assembly and displacement with vincristine. In Aim 3A, we will characterize the pharmacokinetic properties of AG161-
47 and 4 of the most promising analogs from Aim 2. In Aim 3B, we will test the neuroprotective potential of 5 doses of
the single most effective, safe analog from Aims 2-3A, in mice infused with α-synuclein fibrils in the OB/AON. Cognitive,
anxiety, olfactory, and motor behavior will be assessed at baseline and monthly intervals. α-synuclein inclusions and cell
counts will be measured with unbiased stereological tools. Aim 3B will identify a pharmacologically active dose (PAD)
that mitigates inclusions, cell loss, protein...

## Key facts

- **NIH application ID:** 10040472
- **Project number:** 1R21AG068608-01
- **Recipient organization:** DUQUESNE UNIVERSITY
- **Principal Investigator:** ALEEM GANGJEE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,500
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040472

## Citation

> US National Institutes of Health, RePORTER application 10040472, Novel Cytoskeletal Stabilizers as Potential Treatments for Limbic Lewy Body Disorders (1R21AG068608-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10040472. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*