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The Role of NHE1 in Reactive Astrocy...

Collier, Jenelle Monet,

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The Role of NHE1 in Reactive Astrocytes in Alzheimer's Disease /

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Role of NHE1 in Reactive Astrocytes in Alzheimer's Disease // Jenelle Monet Collier.
Author:	Collier, Jenelle Monet,
Description:	1 electronic resource (124 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Neurosciences. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31842276
ISBN:	9798315780748

The Role of NHE1 in Reactive Astrocytes in Alzheimer's Disease /
Collier, Jenelle Monet,

The Role of NHE1 in Reactive Astrocytes in Alzheimer's Disease /Jenelle Monet Collier. - 1 electronic resource (124 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Reactive astrocytes are observed as one of the earliest pathological biomarkers associated with Alzheimer's Disease (AD) development, appearing before amyloid-beta (Aβ) plaque deposition, Tau neurofibrillary tangles, and/or cognitive deficits. As AD progresses, reactive astrocytes abandon their homeostatic roles, and their prolonged transformations are found to contribute to disease pathogenesis including Aβ accumulation, neuroinflammation, and neurodegeneration, yet these underlying pathological mechanisms remain unexplored. Recent studies report that reactive astrocytes upregulate Na+ /H+ Exchanger 1 (NHE1) protein expression, a proton extrusion ion transporter in pH homeostasis, in various neurodegenerative experimental models. Both pharmacological inhibition and transgenic knockout of astrocytic NHE1 protein significantly attenuated astrogliosis and neurodegeneration in these studies. In my initial studies, astrocytic NHE1 deletion reduced LCN2 mediated reactive-astrocyte neurotoxicity in an ischemic stroke mouse model, however, whether modulating astrocyte function through NHE1 activity inhibition can attenuate or prevent AD pathogenesis has not been investigated. In my dissertation project, I first examined changes of NHE1 protein expression in reactive astrocytes in post-mortem AD patient brain tissues and found significantly higher NHE1+ /GFAP+ reactive astrocytes in cerebral cortical tissues compared to control subjects. Then, using the APP/PS1dE9 AD mouse model, I characterized changes of NHE1 protein in astrocytes throughout AD development and detected significantly increased NHE1 protein expression in hippocampal and cortical reactive astrocytes at 8-10 months of age, compared to wild-type (WT) control mice. Interestingly, the NHE1 and GFAP protein expression was significantly elevated in close proximity to Aβ plaques in the APP/PS1dE9 mouse hippocampal and cortical brain regions. APP/PS1dE9 mice displayed hyperactive locomotor activity starting at 4 months old of age, yet pharmacological inhibition of NHE1 protein in APP/PS1dE9 mice significantly decreased hyperactive locomotor activity and Aβ fibril densities by 8 months of age. We further developed the APP/PS1dE9: GFAP-creERT2+/- ; NHE1f/f (APP/PS1dE9-NHE1 KO) mouse line as a new tool to further study efficacy of deletion of NHE1 on AD-associated astrogliosis and Aβ phagocytosis/degradation impairments. Taken together, these findings provide new insights into the role of NHE1 protein in reactive astrocytes' involvement in AD pathogenesis, and present NHE1 protein as a potential target in attenuating reactive astrocytes contributions to neurodegenerative diseases.

English

ISBN: 9798315780748Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Amyloid-beta

The Role of NHE1 in Reactive Astrocytes in Alzheimer's Disease /
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520 $a Reactive astrocytes are observed as one of the earliest pathological biomarkers associated with Alzheimer's Disease (AD) development, appearing before amyloid-beta (Aβ) plaque deposition, Tau neurofibrillary tangles, and/or cognitive deficits. As AD progresses, reactive astrocytes abandon their homeostatic roles, and their prolonged transformations are found to contribute to disease pathogenesis including Aβ accumulation, neuroinflammation, and neurodegeneration, yet these underlying pathological mechanisms remain unexplored. Recent studies report that reactive astrocytes upregulate Na+ /H+ Exchanger 1 (NHE1) protein expression, a proton extrusion ion transporter in pH homeostasis, in various neurodegenerative experimental models. Both pharmacological inhibition and transgenic knockout of astrocytic NHE1 protein significantly attenuated astrogliosis and neurodegeneration in these studies. In my initial studies, astrocytic NHE1 deletion reduced LCN2 mediated reactive-astrocyte neurotoxicity in an ischemic stroke mouse model, however, whether modulating astrocyte function through NHE1 activity inhibition can attenuate or prevent AD pathogenesis has not been investigated. In my dissertation project, I first examined changes of NHE1 protein expression in reactive astrocytes in post-mortem AD patient brain tissues and found significantly higher NHE1+ /GFAP+ reactive astrocytes in cerebral cortical tissues compared to control subjects. Then, using the APP/PS1dE9 AD mouse model, I characterized changes of NHE1 protein in astrocytes throughout AD development and detected significantly increased NHE1 protein expression in hippocampal and cortical reactive astrocytes at 8-10 months of age, compared to wild-type (WT) control mice. Interestingly, the NHE1 and GFAP protein expression was significantly elevated in close proximity to Aβ plaques in the APP/PS1dE9 mouse hippocampal and cortical brain regions. APP/PS1dE9 mice displayed hyperactive locomotor activity starting at 4 months old of age, yet pharmacological inhibition of NHE1 protein in APP/PS1dE9 mice significantly decreased hyperactive locomotor activity and Aβ fibril densities by 8 months of age. We further developed the APP/PS1dE9: GFAP-creERT2+/- ; NHE1f/f (APP/PS1dE9-NHE1 KO) mouse line as a new tool to further study efficacy of deletion of NHE1 on AD-associated astrogliosis and Aβ phagocytosis/degradation impairments. Taken together, these findings provide new insights into the role of NHE1 protein in reactive astrocytes' involvement in AD pathogenesis, and present NHE1 protein as a potential target in attenuating reactive astrocytes contributions to neurodegenerative diseases.
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