# Prevention of complement and immune-mediated Lewy body dementia

> **NIH NIH R01** · MCLEAN HOSPITAL · 2021 · $569,300

## Abstract

Synapses and axons are targets of inflammation-induced neurodegeneration. Synaptic
dysfunction and loss usually precedes degeneration of the neurons, and are early features of
several neurodegenerative diseases including Lewy body disease dementia. Our preliminary
data show that the complement system is activated after elevation of brain glycosphingolipids,
which are involved in the pathophysiology of Lewy body dementia and related disorders. The in
vivo experiments outlined in this proposal determine complement activation, the immune system
and synaptic neurodegeneration in dementia of the Lewy body type. In addition, in these
preclinical animal models, the cognitive effects of inhibiting the complement pathway will be
determined.
We specifically hypothesize that (1) C1q and the complement pathway is involved in synaptic
dysfunction and loss in experimental Lewy body dementia models in which synaptic
degeneration and inflammatory response are key pre-degenerative features, and (2) novel
stabilized, long-acting antisense oligonucleotides can effectively reduce C1qA and C3 in
experimental Lewy body dementia models. These experiments will address whether C1q and
C3 are involved in the degeneration of cortical and hippocampal neurons using (a) global brain
human Thy1 α-synuclein overexpression, (b) regional AAV human α-synuclein expression, and
(c) systemic and brain glycosphingolipid-induced α-synucleinopathy and inflammation using
GbaD409V knockin mice. Cognitive behavioral assays include novel object recognition tasks and
Y-maze. By peripheral and central knockout in experimental Lewy body dementia models these
experiments are also designed to distinguish between the local role of C1q and C3 in
eliminating synapses in the brain (by brain antisense oligonucleotide targeting) and the
potentially needed phagocytic function and systemic influence (by transgenic knockout).
Investigating synaptic loss mediated by modulators of the complement pathway is a paradigm
for understanding cortical and hippocampal neuron degeneration in models of Lewy body and
related dementias. The findings will impact the understanding and therapeutic options to
potentially control complement-mediated elimination of synapses and degeneration of neurons
in Lewy body dementia.

## Key facts

- **NIH application ID:** 10180835
- **Project number:** 5R01AG060195-04
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** PENELOPE Jane HALLETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $569,300
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180835

## Citation

> US National Institutes of Health, RePORTER application 10180835, Prevention of complement and immune-mediated Lewy body dementia (5R01AG060195-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10180835. Licensed CC0.

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