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416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration

OBJECTIVES/GOALS: This project aims to elucidate the mechanism by which LRP1 governs hippocampal neurogenesis with a particular focus on its relevance in brain aging and memory loss. We are specifically interested in further discerning the intricacies of a novel relationship we have discovered betwe...

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Autores principales: Dietert, Kristi, Mahesula, Swetha, Reed, Pamela, Sprague, Shane, Kokovay, Erzsebet, Sayre, Naomi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209069/
http://dx.doi.org/10.1017/cts.2022.242
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author Dietert, Kristi
Mahesula, Swetha
Reed, Pamela
Sprague, Shane
Kokovay, Erzsebet
Sayre, Naomi
author_facet Dietert, Kristi
Mahesula, Swetha
Reed, Pamela
Sprague, Shane
Kokovay, Erzsebet
Sayre, Naomi
author_sort Dietert, Kristi
collection PubMed
description OBJECTIVES/GOALS: This project aims to elucidate the mechanism by which LRP1 governs hippocampal neurogenesis with a particular focus on its relevance in brain aging and memory loss. We are specifically interested in further discerning the intricacies of a novel relationship we have discovered between LRP1 and CXCR4 in adult neural stem cells. METHODS/STUDY POPULATION: For the in vivo studies, we are using a triple-transgenic mouse model in which we knockout LRP1 in adult neural stem cells. This is accomplished using a nestin-driven Cre-ER system in animals with floxed LRP1 and a floxed stop codon preceding a td-tomato reporter. The reporter allows for visualization of cells with the knockout and for trafficking and differentiation assays to be easily accomplished. We study stroke recovery using the middle cerebral artery occlusion model and brain aging by inducing the knockout and allowing the mice to age. We perform behavioral batteries and histological analysis on these mice to elucidate functional changes in neurogenesis. We also incorporate in vitro studies using primary neural stem cell cultures to mechanistically test the role of LRP1 in neural stem cell function. RESULTS/ANTICIPATED RESULTS: We have discovered that neural stem cell LRP1 knockout caused a 10-fold loss of CXCR4 expression in conjunction with deficits in ischemia-stimulated migration from the subventricular zone. We also found that uninjured aged mice lacking neural stem cell LRP1 displayed spatial memory deficits at 9 months of age (6 months after knockout), suggesting dysregulated hippocampal function. Given this, we hypothesize that LRP1 regulates CXCR4 in the subgranular zone NSCs to enhance hippocampal memory function. Ongoing research is testing our hypothesis via hippocampal functional tests and in vitro trafficking/expression assays. We expect our research to elucidate a previously unknown link between three independently identified effectors of neurodegenerative disease: LRP1, CXCR4, and neurogenesis. DISCUSSION/SIGNIFICANCE: The role of LRP1 in Alzheimers disease has long eluded clarity despite its known role in trafficking many major disease players – ApoE, amyloid beta and tau. Elucidating its role in hippocampal neurogenesis, a potential disease-modifying process, could lead to novel therapeutic approaches in diseases that cause the death of 1/3 of senior citizens.
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spelling pubmed-92090692022-07-01 416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration Dietert, Kristi Mahesula, Swetha Reed, Pamela Sprague, Shane Kokovay, Erzsebet Sayre, Naomi J Clin Transl Sci Valued Approaches OBJECTIVES/GOALS: This project aims to elucidate the mechanism by which LRP1 governs hippocampal neurogenesis with a particular focus on its relevance in brain aging and memory loss. We are specifically interested in further discerning the intricacies of a novel relationship we have discovered between LRP1 and CXCR4 in adult neural stem cells. METHODS/STUDY POPULATION: For the in vivo studies, we are using a triple-transgenic mouse model in which we knockout LRP1 in adult neural stem cells. This is accomplished using a nestin-driven Cre-ER system in animals with floxed LRP1 and a floxed stop codon preceding a td-tomato reporter. The reporter allows for visualization of cells with the knockout and for trafficking and differentiation assays to be easily accomplished. We study stroke recovery using the middle cerebral artery occlusion model and brain aging by inducing the knockout and allowing the mice to age. We perform behavioral batteries and histological analysis on these mice to elucidate functional changes in neurogenesis. We also incorporate in vitro studies using primary neural stem cell cultures to mechanistically test the role of LRP1 in neural stem cell function. RESULTS/ANTICIPATED RESULTS: We have discovered that neural stem cell LRP1 knockout caused a 10-fold loss of CXCR4 expression in conjunction with deficits in ischemia-stimulated migration from the subventricular zone. We also found that uninjured aged mice lacking neural stem cell LRP1 displayed spatial memory deficits at 9 months of age (6 months after knockout), suggesting dysregulated hippocampal function. Given this, we hypothesize that LRP1 regulates CXCR4 in the subgranular zone NSCs to enhance hippocampal memory function. Ongoing research is testing our hypothesis via hippocampal functional tests and in vitro trafficking/expression assays. We expect our research to elucidate a previously unknown link between three independently identified effectors of neurodegenerative disease: LRP1, CXCR4, and neurogenesis. DISCUSSION/SIGNIFICANCE: The role of LRP1 in Alzheimers disease has long eluded clarity despite its known role in trafficking many major disease players – ApoE, amyloid beta and tau. Elucidating its role in hippocampal neurogenesis, a potential disease-modifying process, could lead to novel therapeutic approaches in diseases that cause the death of 1/3 of senior citizens. Cambridge University Press 2022-04-19 /pmc/articles/PMC9209069/ http://dx.doi.org/10.1017/cts.2022.242 Text en © The Association for Clinical and Translational Science 2022 https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
spellingShingle Valued Approaches
Dietert, Kristi
Mahesula, Swetha
Reed, Pamela
Sprague, Shane
Kokovay, Erzsebet
Sayre, Naomi
416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration
title 416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration
title_full 416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration
title_fullStr 416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration
title_full_unstemmed 416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration
title_short 416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration
title_sort 416 lrp1 as a modulator of hippocampal neurogenesis and neurodegeneration
topic Valued Approaches
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209069/
http://dx.doi.org/10.1017/cts.2022.242
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