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Determinants of the Proteolytic Degradation of Soluble Amyloid-beta

Award Number: R15AG055043
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2021

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Determinants of the Proteolytic Degradation of Soluble Amyloid-beta - ABSTRACT The amyloid-β protein (Aβ) is the most studied amyloid peptide because of its strong association with the neurodegeneration that occurs in Alzheimer’s disease (AD). Abnormally folded Aβ accumulates in the extracellular space to form insoluble amyloid plaques. However, the lack of correlation between the amount and location of the insoluble amyloid plaques and neurodegeneration has led to the hypothesis that small, soluble, oligomeric assemblies consisting of a mixture of Aβ peptides, termed soluble Aβ, are responsible for the death of neurons. We hypothesize that sporadic AD (aka late-onset AD), which accounts for the majority of AD cases, results from the rise in soluble Aβ levels in the brain. A second hypothesis is that the rise in soluble Aβ levels results in part from an age-dependent decline of the proteolytic degradation of soluble Aβ. If these hypotheses are true, then enhancing the proteolytic degradation of soluble Aβ would be an attractive strategy in the prevention and treatment of sporadic AD. The development of this strategy requires knowledge of the determinants of the proteolytic degradation of soluble Aβ. Based on extensive preliminary data, we will test two hypotheses. In Specific Aim 1, we will test the hypothesis that the composition of Aβ species in soluble Aβ is an important determinant of the proteolytic degradation of soluble Aβ. This specific aim has three sub-aims: (Aim 1.1) To test the hypothesis that the presence of pyroglutamate-3 Aβ in soluble Aβ diminishes the proteolytic degradation of soluble Aβ; (Aim 1.2) To determine the biophysical basis for the diminished proteolytic degradation of soluble Aβ containing pyroglutamate-3 Aβ; and (Aim 1.3) To test the hypothesis that the proteolytic degradation of soluble Aβ containing pyroglutamate-3 Aβ to can be enhanced by small molecules including polyphenols and adenosine triphosphate. In Specific Aim 2, we will test the hypothesis that the composition of neuronal membranes is an important determinant of the proteolytic degradation of soluble Aβ. This specific aim has three sub-aims: (Aim 2.1) To test the hypothesis that the presence of GM1 ganglioside in membranes diminishes the proteolytic degradation of soluble Aβ; (Aim 2.2) To determine the susceptibility of β- sheet assemblies formed in the presence of membranes containing GM1 ganglioside to proteolytic degradation; and (Aim 2.3) To test the hypothesis that the proteolytic degradation of soluble Aβ and β-sheet assemblies formed in the presence of membranes containing GM1 ganglioside can be enhanced by small molecules including polyphenols and adenosine triphosphate. The execution of the aims of this proposal will facilitate the development of preventive and therapeutic strategies that work by preventing the age-dependent decline of the proteolytic degradation of soluble Aβ associated with sporadic AD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$60 )
2023	2018	TRUSTEES OF CLARK UNIVERSITY	950 MAIN ST	WORCESTER	MA	01610	WORCESTER	USA	Aging Research	000	1	11/21/2022	NEW	-$60
														Subtotal = -$60

Issue Date FY: 2022 ( Subtotal = -$104 )
2022	2018	TRUSTEES OF CLARK UNIVERSITY	950 MAIN ST	WORCESTER	MA	01610	WORCESTER	USA	Aging Research	000	1	4/8/2022	NEW	-$104
														Subtotal = -$104

Issue Date FY: 2018 ( Subtotal = $375,750 )
2018	2018	TRUSTEES OF CLARK UNIVERSITY	950 MAIN ST	WORCESTER	MA	01610	WORCESTER	USA	Aging Research	000	1	2/27/2018	NEW	$375,750
														Subtotal = $375,750

Grand Total All Awards = $375,586

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Determinants of the Proteolytic Degradation of Soluble Amyloid-beta

Award Number: R15AG055043

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2021

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