Investigating the mechanisms and impact of amyloid-beta mediated disruption of synaptic nanoachitecture

Active Project Grant Awarded Last action

Award ID
F31NS141417
Recipient
Awarding agency
Obligated
$250,401

Award facts

Completion date 93% complete
Place of performance
Aurora, CO 80045, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The nanoscale organization of key synaptic proteins is now considered an important contributor to synaptic activity and plasticity. However, there is a lack of research on how such delicate nano-organization might be involved in brain diseases, which often directly impact synaptic function. Alzheimer's disease (ad) is associated with brain accumulation of the amyloid-beta (ASS) peptide. Furthermore, oligomeric assemblies of the 42 amino acid variant, ASS42, which directly target synapses, have been found especially pernicious toward synaptic function. In preliminary research, i have observed through multiple replicates that a brief, 15-minute application of 500 NM ASS is sufficient to disrupt existing synaptic nanostructure. This manifests as the addition of nanoscale objects of the PSD95 scaffolding protein, and of GLUA1 subunit-containing ampa-type glutamate receptors, a phenomenon we have titled, "fragmentation". As this observation occurs along the same timescale as ASS- mediated nmda-type glutamate receptor dysfunction and deficits to LTP (long-term potentiation), i hypothesize that ASS-mediated fragmentation of synaptic nanostructure ultimately leads to deficits in synapse function and plasticity. In this proposal, i aim to thoroughly characterize both the kinetics, and dose-response of ASS-mediated fragmentation, as well as to what extent this fragmentation occurs (i.e., does fragmentation include select synaptic proteins, or completely restructure synaptic nanoarchitecture). I also plan to assess what signaling mechanisms underlie ASS-mediated fragmentation and whether these are similar, or distinct from already established mechanisms causing ASS-mediated synaptic dysfunction. Lastly, my preliminary data show that i can prevent the fragmentation of ampar nanostructure at the synapse by crosslinking receptors with a GLUA1 antibody prior to ASS exposure. Using this method, as well as others our lab has developed, i will then test whether ASS-mediated synaptic nanostructure fragmentation is responsible for LTP deficits and synapse loss. Importantly, this fellowship proposal provides the opportunity for my extensive training in multiple experimental techniques including: super-resolution microscopy (multicolor and live-cell sted imaging, including preparation of sted-DYE conjugated primary antibodies), writing computer based imaging-analyses, receptor signaling pharmacology, molecular cloning (crispr-based knockout / knockin strategies, optogenetic / chemogenetic construct design), electrophysiology and CA2+ imaging, and 2-photon glutamate uncaging.

Transactions

Action Obligated Date
Amendment $480
Amendment $32,437
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Amendment $0
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Amendment $36,671
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Original award $36,671
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Quick answers

Who received award F31NS141417?

F31NS141417 was awarded to The Regents Of The University Of Colorado by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on July 23, 2025.

How much is award F31NS141417 worth?

$250,401 has been obligated on F31NS141417.

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