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From a Venom to a Potential Treatment for Alzheimer's Disease

Award Number: R03AG054950
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2021

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From a Venom to a Potential Treatment for Alzheimer's Disease - Project Summary Build-up of amyloid beta (Aß) plaque in the brain is a hallmark feature of Alzheimer's disease. Research indicates that Aß build-up is the result of inefficient clearance of Aß as opposed to increased production. Breakdown by enzymes is one mechanism by which Aß is cleared. Although several Aß degrading enzymes have been identified, neprilysin (NEP) is the most physiologically relevant. Stimulating the activity of these enzymes is therefore a potential approach for the therapeutic manipulation of Aß levels. However, at present there are no chemical compounds that can directly stimulate the activity of Aß clearing enzymes. We have previously reported the discovery of a peptide (referred to as K49-P1-20) from a snake venom, which directly stimulates activity of NEP and its closest homolog endothelin converting enzyme (ECE). Our preliminary data indicate that K49-P1-20 can prevent the formation of Aß plaque in a mouse model of Alzheimer's disease. Our published data indicate that replacing residue 9 of K49-P1-20 with Ala (Ala9K49-P1-20) can increase its potency and selectivity for NEP compared with ECE. Aim 1: To examine the selectivity of Ala9 K49-P1-20. We will examine the effect of increasing concentrations of Ala9 K49-P1-20 on the activity of each of the following enzymes which are also known to cleave Aß: ECE-2, insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE), MMP2 and MMP9. Initially enzyme activity will be measured using quenched fluorescent substrate based assays. Mass spectrometry will be used to determine the rate of Aß cleavage by each of these enzymes in the presence or absence of Ala9 K49-P1-20. Aim 2: To determine the ability of Ala9K49-P1-20 to prevent the formation of Aß plaques and associated behavioural impairments in a mouse model of AD. K49-P1-20 will be administered directly into the brain of B6C3-Tg(APPswe,PSEN1dE9)85Dbo mice via osmotic mini pumps. Drug infusion will begin prior to the formation of plaque and behavioral changes (at 4 months of age), and continue for 16 weeks. Mice will be subjected to the 8 arm radial maize test prior to treatment (T=0), and every 2 months thereafter in order to determine the effect of treatment on cognitive function. At the end of the treatment period, mice will be scarified, brain tissues removed and processed to determine amyloid beta levels. Above work will lay the foundation for a range of future studies which include understanding the mechanism behind enzyme stimulation, the development of peptidemimetics and most importantly the ability to REVERSE or halt the progression of Alzheimer's disease.


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: 2022 ( Subtotal = $0 )
2022	2019	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC			AUS	Aging Research	000	2	4/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC			AUS	Aging Research	000	2	4/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $53,525 )
2019	2019	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC	3168		AUS	Aging Research	000	2	5/21/2019	NON-COMPETING CONTINUATION	$53,525
														Subtotal = $53,525

Issue Date FY: 2018 ( Subtotal = $53,559 )
2018	2018	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC	3168		AUS	Aging Research	000	1	9/15/2018	NEW	$53,559
														Subtotal = $53,559

Grand Total All Awards = $107,084

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From a Venom to a Potential Treatment for Alzheimer's Disease

Award Number: R03AG054950

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2021

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