LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4

Hiroshi Oue; Yu Yamazaki; Wenhui Qiao; Chen Yuanxin; Yingxue Ren; Aishe Kurti; Francis Shue; Tammee M Parsons; Ralph B Perkerson; Keiji Kawatani; Ni Wang; Skylar C Starling; Bhaskar Roy; Ioana-Emilia Mosneag; Tomonori Aikawa; Marie-Louise Holm; Chia-Chen Liu; Yasuteru Inoue; Patrick M Sullivan; Yan W Asmann; Betty Ys Kim; Guojun Bu; Takahisa Kanekiyo

doi:10.1172/jci.insight.163822

LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4

Hiroshi Oue, Yu Yamazaki, Wenhui Qiao, Chen Yuanxin, Yingxue Ren, Aishe Kurti, Francis Shue, Tammee M Parsons, Ralph B Perkerson, Keiji Kawatani, Ni Wang, Skylar C Starling, Bhaskar Roy, Ioana-Emilia Mosneag, Tomonori Aikawa, Marie-Louise Holm, Chia-Chen Liu, Yasuteru Inoue, Patrick M Sullivan, Yan W AsmannBetty Ys Kim, Guojun Bu, Takahisa Kanekiyo

Division of Neuroscience

Research output: Contribution to journal › Article › peer-review

Abstract

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.

Original language	English
Journal	JCI Insight
Volume	8
Issue number	7
DOIs	https://doi.org/10.1172/jci.insight.163822
Publication status	Published - 10 Apr 2023

Keywords

Alzheimer disease
Dementia
Mouse models
Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1172/jci.insight.163822Licence: CC BY

Cite this

Oue, H., Yamazaki, Y., Qiao, W., Yuanxin, C., Ren, Y., Kurti, A., Shue, F., Parsons, T. M., Perkerson, R. B., Kawatani, K., Wang, N., Starling, S. C., Roy, B., Mosneag, I.-E., Aikawa, T., Holm, M.-L., Liu, C.-C., Inoue, Y., Sullivan, P. M., ... Kanekiyo, T. (2023). LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4. JCI Insight, 8(7). https://doi.org/10.1172/jci.insight.163822

@article{2498eb8a42eb49a7992289a82cf745a2,

title = "LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4",

abstract = "Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.",

keywords = "Alzheimer disease, Dementia, Mouse models, Neuroscience",

author = "Hiroshi Oue and Yu Yamazaki and Wenhui Qiao and Chen Yuanxin and Yingxue Ren and Aishe Kurti and Francis Shue and Parsons, {Tammee M} and Perkerson, {Ralph B} and Keiji Kawatani and Ni Wang and Starling, {Skylar C} and Bhaskar Roy and Ioana-Emilia Mosneag and Tomonori Aikawa and Marie-Louise Holm and Chia-Chen Liu and Yasuteru Inoue and Sullivan, {Patrick M} and Asmann, {Yan W} and Kim, {Betty Ys} and Guojun Bu and Takahisa Kanekiyo",

year = "2023",

month = apr,

day = "10",

doi = "10.1172/jci.insight.163822",

language = "English",

volume = "8",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "American Society for Clinical Investigation",

number = "7",

}

Oue, H, Yamazaki, Y, Qiao, W, Yuanxin, C, Ren, Y, Kurti, A, Shue, F, Parsons, TM, Perkerson, RB, Kawatani, K, Wang, N, Starling, SC, Roy, B, Mosneag, I-E, Aikawa, T, Holm, M-L, Liu, C-C, Inoue, Y, Sullivan, PM, Asmann, YW, Kim, BY, Bu, G & Kanekiyo, T 2023, 'LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4', JCI Insight, vol. 8, no. 7. https://doi.org/10.1172/jci.insight.163822

TY - JOUR

T1 - LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4

AU - Oue, Hiroshi

AU - Yamazaki, Yu

AU - Qiao, Wenhui

AU - Yuanxin, Chen

AU - Ren, Yingxue

AU - Kurti, Aishe

AU - Shue, Francis

AU - Parsons, Tammee M

AU - Perkerson, Ralph B

AU - Kawatani, Keiji

AU - Wang, Ni

AU - Starling, Skylar C

AU - Roy, Bhaskar

AU - Mosneag, Ioana-Emilia

AU - Aikawa, Tomonori

AU - Holm, Marie-Louise

AU - Liu, Chia-Chen

AU - Inoue, Yasuteru

AU - Sullivan, Patrick M

AU - Asmann, Yan W

AU - Kim, Betty Ys

AU - Bu, Guojun

AU - Kanekiyo, Takahisa

PY - 2023/4/10

Y1 - 2023/4/10

N2 - Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.

AB - Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.

KW - Alzheimer disease

KW - Dementia

KW - Mouse models

KW - Neuroscience

U2 - 10.1172/jci.insight.163822

DO - 10.1172/jci.insight.163822

M3 - Article

C2 - 37036005

SN - 2379-3708

VL - 8

JO - JCI Insight

JF - JCI Insight

IS - 7

ER -

LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this