# Chemical Fingerprints of Cognitive Impairment-related alpha-Synuclein Strains using 3D Small Molecule Microarray and Related Therapeutic Application

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $450,313

## Abstract

PROJECT SUMMARY
Dementia has significant social and economic implications in terms of direct medical and social care costs. Lewy
bodies dementia (LBD) is one of the most common causes of dementia, including Parkinson's disease with
dementia (PDD) and dementia with Lewy bodies (DLB). Approximately 30% of Alzheimer' disease (AD) patients
also suffer from LBD resulting in a more rapid and severe cognition decline than AD alone. LBD is associated
with abnormal deposits of a protein called α-synuclein (α-syn) in the brain. Substantial postmortem studies by
Braak et al. show that α-syn pathology spreads in a stereotypical fashion in PDD, and the onset of motor
symptoms occurs with loss of dopaminergic neurons in the substantia nigra (SN), and ~80% of patients finally
progress to PDD with α-syn pathology in the cortex. In brief, the spread of pathogenic α-syn acts as a major
driver of cognitive impairment (CI) in LBD. Recent studies support the notion that pathogenic α-syn may behave
in a manner similar to strain-specific prions exhibiting distinct biochemical and pathologic phenotypes. Even
recombinant α-syn aggregates (one strain) can convert to another strain after cyclic aggregation, and these two
strains exhibited different neurotoxicity and immunoblot patterns after digestion with proteinase K. When injected
intracerebrally, MSA (multiple system atrophy) brain homogenates remarkably promote α-syn pathology
spreading compared to PD homogenates, suggesting that MSA and PD have different strains of α-syn. Strain-
specific difference were observed in the signs of neurological illness, time to disease onset, morphology of
cerebral α-syn deposits and the conformation properties of the induced aggregates. Moreover, different strains
targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting
observed among α-synucleinopathies. To investigate the role of α-syn strains in PDD progression, we collected
cerebrospinal fluid (CSF) samples from the clinically well-characterized patients followed longitudinally. In a
double-blinded manner, we amplified α-syn aggregates templated by CSF (containing α-syn seeds) of patients,
using a well-established strain amplification technique--PMCA (protein misfolding cyclic amplification). We
characterized these α-syn aggregates from patients with well-established neurotoxicity, biochemical, and
biophysical assays. However, given that misfolded α-syn aggregates exhibit heterogeneous strain properties
and dynamic conversion, particularly in the complicated interplay with environmental, genetic, aging factors, it is
necessary to build a fingerprinting method to define these α-syn strains from LBD patients. Fortunately, small
molecule microarray (SMM) screening has provided a platform to combine the affinity profile of a diverse panel
of tens of thousands of small molecules to certain protein targets. Analysis of this “big data” by comparing and
contracting these affinity probes...

## Key facts

- **NIH application ID:** 10360139
- **Project number:** 1R21NS125559-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xiaobo Mao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $450,313
- **Award type:** 1
- **Project period:** 2022-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360139

## Citation

> US National Institutes of Health, RePORTER application 10360139, Chemical Fingerprints of Cognitive Impairment-related alpha-Synuclein Strains using 3D Small Molecule Microarray and Related Therapeutic Application (1R21NS125559-01). Retrieved via AI Analytics 2026-07-28 from https://api.ai-analytics.org/grant/nih/10360139. Licensed CC0.

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