자료유형  

 학위논문

Control Number  

0016934749

International Standard Book Number  

9798380391993

Dewey Decimal Classification Number  

616

Main Entry-Personal Name  

Zhou, Andrew.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Minnesota., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(197 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

General Note  

Advisor: Kandimalla, Karunya K.

Dissertation Note  

Thesis (Ph.D.)--University of Minnesota, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Several major risk factors have emerged for Alzheimer's disease (AD), including advanced age and metabolic syndromes like cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Blood-brain barrier (BBB) dysfunction is a shared feature among these disorders and precedes the emergence of histopathological hallmarks and cognitive decline in AD patients. Endogenous proteins like apolipoprotein A-I (ApoA-I), insulin, and amyloid-β (Aβ) peptides are heavily implicated in AD, and play key roles in CVD, T2DM and cerebral amyloid angiopathy, respectively. However, the mechanisms governing the BBB transport and function of these key proteins are poorly understood. Further, it is unclear how these mechanisms are altered by major AD risk factors.My thesis seeks to identify key mechanisms governing the transport and function of ApoA-I, insulin and Aβ peptides at the BBB, under healthy conditions and in the presence of various AD risk factors that are associated with peripheral insulin resistance. This involved pharmacokinetic experiments using 125I radiolabeled proteins in rodent models representing various AD risk factors, alongside in vitro transport and signaling studies performed using an in vitro BBB cell model. Findings from Chp. 2 showed that the BBB plays a major role in ApoA-I brain delivery in rats, refuting a recent claim that blood-CSF barrier is the major portal for ApoA-I brain delivery. Findings from Chp. 3 showed that aging is associated with reduced insulin brain delivery and increased brain Aβ accumulation, which is expected to contribute to AD progression. Findings from Chp. 4 showed that insulin brain delivery is reduced in T2DM or AD mouse models compared to the healthy controls, with the lowest insulin brain delivery observed in mice that manifest. Further, these reductions in brain insulin delivery were associated with deficits in insulin signaling pathways at the BBB, based on western blots performed on brain microvessels harvested from the different mouse models.Findings from Chp. 5 provided a functional validation of the importance of insulin signaling pathways in regulating insulin and Aβ peptide transport at the BBB. In healthy mice, treatment with an insulin signaling inhibitor reduced brain insulin delivery and increased brain Aβ accumulation, recapitulating the trends observed in the mouse models of AD risk factors. This was supported by in vitro studies performed in BBB cell monolayers. Further, insulin uptake was reduced upon direct inhibition of the insulin receptor, but not by inhibition of either or both downstream signaling arms, specifically the PI3K/AKT and MAPK/ERK pathways. Additionally, the inhibitory effects of Aβ peptides on insulin uptake in the BBB cell monolayers were characterized.Finally, the mechanisms of action of two different potential approaches for reducing brain Aβ levels as a treatment for AD were explored. Findings from Chp. 6 showed the ApoA-I mimetic peptide 4F has substantially greater brain permeability compared to full-length ApoA-I in healthy mice. The 4F was further shown to beneficially modulate the transport of Aβ40 and Aβ42 peptides in healthy mice, which was confirmed using an in vitro BBB cell model. Findings from Chp. 7 showed that systemic treatment with an anti-Aβ monoclonal antibody led to sequestration of plasma Aβ and reduced brain Aβ accumulation in healthy mice. This offers mechanistic insight into the previously established "sink effect" of Aβ immunotherapies on brain Aβ clearance.Together, these findings provide novel mechanistic insights into how AD risk factors contribute to BBB dysfunction, and how therapeutic agents like ApoA-I mimetic peptides and Aβ immunotherapies could potentially be used to restore BBB function.

Subject Added Entry-Topical Term  

Pharmaceutical sciences.

Subject Added Entry-Topical Term  

Neurosciences.

Subject Added Entry-Topical Term  

Epidemiology.

Index Term-Uncontrolled  

Alzheimer's disease

Index Term-Uncontrolled  

Cardiovascular disease

Index Term-Uncontrolled  

Blood-brain barrier

Index Term-Uncontrolled  

Diabetes

Index Term-Uncontrolled  

Metabolic syndromes

Added Entry-Corporate Name  

University of Minnesota Pharmaceutics

Host Item Entry  

Dissertations Abstracts International. 85-03B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

로그인을 한후 보실 수 있는 자료입니다.

Control Number  

joongbu:644055