# Novel fibril-selective nanobody-based agents targeting intracellular and extracellular α-synuclein aggregates and prion-like propagation induced dementia

> **NIH NIH RF1** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $2,280,379

## Abstract

Summary
Lewy Body Dementias (LBDs) are a series of neurodegenerative disorders characterized by accumulation of
misfolded α‐synuclein (αS), including Dementia with Lewy Body (DLB), Parkinson’s Disease with Dementia
(PDD), and 1/3 of Alzheimer’s Disease (AD). DLB is the 2nd most common dementia after AD accounting for 30%
of dementia cases; approximately 30% of AD cases suffer from α‐synucleinopathy resulting in a more rapid and
severe cognitive decline than AD alone. In brief, αS pathology is highly associated with AD and related dementias
(ADRD). Braak et al. identified that αS pathology spreading as disease progresses from a substantial number of
postmortem studies. Experimental studies have further demonstrated that misfolded αS seeds (i.e., brain
extracts, recombinant αS preformed fibrils (PFF) are prion-like particles that can exponentially propagate
pathology cell-to-cell, tissue-to-tissue, inducing neuroinflammation and neurodegeneration, driving the disease
progression and causing dementia. These αS seeds can enter cells and induce endogenous αS monomer
misfolding and aggregation, assessed with the immunoreactivity of anti-αS phosphorylated serine 129 (pS129),
a widely used pathological marker. The induced intracellular seeds can be released to extracellular spaces, and
then the extracellular seeds start a new cycle of cell-to-cell transmission. Because intracellular and extracellular
seeds can be easily interconverted, it brings the difficulty to cease cell-to-cell transmission of pathogenic αS. αS
pathology and propagation are observed mainly inside neurons, and αS is more abundant in neurons than in
glial cells, indicating that the intraneuronal αS significantly drives the pathogenesis. There have been
tremendous efforts on the development of antibodies against αS; however, due to the large size and structural
complexity, antibodies have limited penetrability through the plasma membrane. αS antibodies do not enter cells
and are inaccessible to intracellular αS seeds, but only to extracellular αS seeds. Furthermore, antibodies are
usually not functional in the reducing environment of the cytosol due to the reduction of the disulfide bonds,
which are critical for the correct folding of antibodies. In addition, antibody treatment could be costly and
inconvenient in long-term disease progression. It is hypothesized that blockage of intracellular αS propagation
could be effective against cell-to-cell αS transmission, and all these gaps indicate an urgent need to generate a
reagent targeting the intracellular pathogenic αS. In this application, we aim to develop novel nanobody-based
agents that can targeting these pathogenic αS to block cell-to-cell transmission.

## Key facts

- **NIH application ID:** 10882038
- **Project number:** 1RF1NS137428-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Xiaobo Mao
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,280,379
- **Award type:** 1
- **Project period:** 2024-09-19 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882038

## Citation

> US National Institutes of Health, RePORTER application 10882038, Novel fibril-selective nanobody-based agents targeting intracellular and extracellular α-synuclein aggregates and prion-like propagation induced dementia (1RF1NS137428-01). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10882038. Licensed CC0.

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