Grants and Contracts Details
Description
Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and build-up of Aâ peptides,
amyloid plaques, and neurofibrillary tau tangles. Current strategies to prevent Aâ formation or secretion are not
successful. Preventing Aâ build-up while enhancing Aâ uptake and clearance is an alternative approach to
minimize the effect of Aâ peptides. A critical barrier to progress in the development of novel drugs that
prevent Aâ build-up and improve clearance is the lack of a thorough understanding of how Aâ amyloid plaques
are nucleated and proliferate instead of Aâ being taken up and cleared by glial cells. Our goal is to interrupt
amyloid plaque nucleation and propagation to enhance Aâ clearance and delay the onset and reduce
neurodegeneration in AD. Our central hypothesis is that ceramide-enriched exosomes secreted by astrocytes
form complexes with Aâ (Aâ/Exos) that function as “seeds” to catalyze nucleation and propagation of
neurotoxic plaques instead of facilitating Aâ transport and clearance by microglia. Secretion, aggregation, and
neurotoxicity of Aâ/Exos is enhanced by elevation of ceramide levels, in particular by neutral sphingomyelinase
2 (nSMase2), an enzyme generating ceramide when activated by Aâ. Drug (e.g., nSMase2 inhibitor)-induced
reduction of ceramide will prevent Aâ/Exo build-up/spreading and protect neurons, which is a novel treatment
option for AD. Our objectives are to 1) test key regulatory factors that control secretion of exosomes and their
association with Aâ; 2) test a novel molecular mechanism by which Aâ/Exos induce plaque formation, tau
hyperphosphorylation, and neuronal cell death; 3) test pharmacological drugs that prevent exosome secretion,
Aâ/Exo-induced plaque formation, tau hyperphosphorylation, and neuronal cell death in vitro and in vivo; and
4) test if Aâ/Exos in serum and cerebrospinal fluid from AD model mice and AD patients can be used as a
novel diagnostic tool for monitoring plaque and tangle build-up, and treatment success. Our expected
outcomes include 1) determining an exosome composition that induces association with Aâ, plaque
nucleation and propagation, tau hyperphosphorylation, and neuronal cell death; 2) identifying ceramidemodulating
drugs that prevent Aâ/Exo-induced plaque formation, tau hyperphosphorylation, and neuronal cell
death; and 3) defining a level of Aâ/Exos in serum that indicates severity of AD and success of treatment.
The impact of this project on public health will include knowledge needed for the development of new
strategies and treatments that could delay and reduce the onset of progressive neurodegeneration in AD. We
will test by which mechanism ceramide promotes association and aggregation of Aâ42 (Aim 1), how Aâ42/Exos
induce plaque formation and neurodegeneration (Aim 2), and which treatment prevents exosome-induced
amyloid aggregation, plaque formation, and AD pathology (Aim 3).
Status | Finished |
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Effective start/end date | 9/1/10 → 2/28/22 |
Funding
- National Institute on Aging: $1,723,396.00
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