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Amyloid beta peptides and type-2 diabetes sequelae synergistically inhibit insulin signaling and trafficking at the blood brain barrier

Award Number: R01NS125437
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Amyloid beta peptides and type-2 diabetes sequelae synergistically inhibit insulin signaling and trafficking at the blood brain barrier - PROJECT SUMMARY Type-2 diabetes mellitus (T2DM) sequelae damage the cerebral microvasculature and augment Alzheimer's pathology by inducing brain insulin resistance characterized by sub-physiological insulin levels and impaired insulin-signaling in the brain. Conversely, soluble amyloid beta (sAβ) peptides that accumulate in the plasma and brain during Alzheimer's progression exacerbate the impact of T2DM and aggravate brain insulin resistance. A critical need exists to identify how T2DM sequelae and sAβ exposure inhibit insulin delivery to the brain and intensify brain insulin resistance. The long-term goal is to elucidate cerebrovascular and metabolic contributions to Alzheimer's disease and facilitate the development of novel therapeutic interventions. The overall objective in this application is to determine the combined effects of T2DM sequelae and sAβ on insulin delivery to the brain and to identify the underlying cellular and molecular mechanisms. The central hypothesis is that T2DM sequelae and sAβ peptides perturb insulin signaling/trafficking at the cerebrovascular endothelium [referred to as the blood brain barrier (BBB)] and reduce insulin delivery to the brain. It is also hypothesized that these effects are further aggravated by the pathological synergism between T2DM sequelae and sAβ. The rationale for the proposed research is that a mechanistic understanding of how sAβ exposure and T2DM sequelae disrupt brain insulin delivery will allow us to develop novel therapeutic strategies to address brain insulin resistance in Alzheimer's disease and T2DM. Guided by preliminary data, the following three specific aims are proposed: 1) Determine the effect of T2DM sequelae on insulin trafficking/signaling at the BBB; 2) Determine the effects of sAβ alone and in conjunction with T2DM sequelae on insulin trafficking/signaling at the BBB; and 3) Identify insulin trafficking pathways at the BBB, vulnerable to sAβ exposure and impaired insulin signaling. Under the first and second aims, dynamic SPECT/CT imaging will be used to characterize insulin uptake kinetics at the BBB in mouse models that exhibit T2DM and Alzheimer's sequelae. Moreover, the dysregulation in insulin signaling at the BBB will be captured by reverse phase protein arrays. For the third aim, flow cytometry and TIRF microscopy will be used to determine the effects of sAβ ± insulin signaling inhibitors on insulin transcytosis in BBB monolayers. The proposed research is potentially innovative because it employs dynamic imaging methods coupled with quantitative modeling techniques to capture changes in insulin trafficking kinetics at the BBB in T2DM and Alzheimer's mouse models. The proposed research is significant because the contribution it is expected to have broad translational importance in repurposing existing drugs to treat brain insulin resistance and in identifying candidate targets to discover novel drugs. Upon completion of the work, the new knowledge generated is expected to have an important positive impact by facilitating the identification of novel therapeutic strategies to combat brain insulin resistance in Alzheimer's patients with T2DM.


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: 2025 ( Subtotal = $478,190 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/19/2025	NON-COMPETING CONTINUATION	$478,190
														Subtotal = $478,190

Issue Date FY: 2024 ( Subtotal = $529,773 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/11/2024	NON-COMPETING CONTINUATION	$52,978
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/8/2024	NON-COMPETING CONTINUATION	$476,795
														Subtotal = $529,773

Issue Date FY: 2023 ( Subtotal = $529,773 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/27/2023	NON-COMPETING CONTINUATION	$529,773
														Subtotal = $529,773

Issue Date FY: 2022 ( Subtotal = $549,723 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/15/2022	NEW	$549,723
														Subtotal = $549,723

Grand Total All Awards = $2,087,459

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Amyloid beta peptides and type-2 diabetes sequelae synergistically inhibit insulin signaling and trafficking at the blood brain barrier

Award Number: R01NS125437

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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