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Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease

Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease
Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease
We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer’s disease (AD) and vascular dementia (VaD), in superior temporal cortex (BA22) from AD (n = 75), VaD (n = 22) and age-matched controls (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in AD and VaD: interleukin (IL)-15 and IL-17A were maximally elevated in end-stage Alzheimer’s disease (Braak tangle stage V-VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III-IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in AD with systemic infection. Cerebral hypoperfusion, indicated by decreased myelin-associated glycoprotein:proteolipid protein-1 (MAG:PLP1) and increased vascular endothelial growth factor-A (VEGF), and blood-brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in AD and VaD, and also in non-dementia controls, with systemic infection. Aβ42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing interferon-γ (IFN-γ), IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of AD, and with infection (even in BS 0-II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in AD; these were related to Aβ level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and BBB leakiness associated with AD and VaD, independently of the level of insoluble Aβ. Our findings highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.
0006-8950
Asby, Daniel J.
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Boche, Delphine
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Allan, Stuart
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Love, Seth
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Miners, Scott
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Asby, Daniel J.
cf0462d7-e923-45eb-b4ce-7c1673f544d5
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Allan, Stuart
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Love, Seth
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Miners, Scott
5cc32095-fb2d-4a1e-9391-52e9b476fa98

Asby, Daniel J., Boche, Delphine, Allan, Stuart, Love, Seth and Miners, Scott (2021) Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease. Brain, [BRAIN-2020-01836.R1]. (In Press)

Record type: Article

Abstract

We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer’s disease (AD) and vascular dementia (VaD), in superior temporal cortex (BA22) from AD (n = 75), VaD (n = 22) and age-matched controls (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in AD and VaD: interleukin (IL)-15 and IL-17A were maximally elevated in end-stage Alzheimer’s disease (Braak tangle stage V-VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III-IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in AD with systemic infection. Cerebral hypoperfusion, indicated by decreased myelin-associated glycoprotein:proteolipid protein-1 (MAG:PLP1) and increased vascular endothelial growth factor-A (VEGF), and blood-brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in AD and VaD, and also in non-dementia controls, with systemic infection. Aβ42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing interferon-γ (IFN-γ), IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of AD, and with infection (even in BS 0-II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in AD; these were related to Aβ level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and BBB leakiness associated with AD and VaD, independently of the level of insoluble Aβ. Our findings highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.

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BRAIN-2020-01836.R1 - Accepted Manuscript
Restricted to Repository staff only until 19 February 2022.
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Accepted/In Press date: 19 February 2021

Identifiers

Local EPrints ID: 447117
URI: http://eprints.soton.ac.uk/id/eprint/447117
ISSN: 0006-8950
PURE UUID: 5af50876-e009-4304-a477-0f2cd5b22282
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

Catalogue record

Date deposited: 03 Mar 2021 17:32
Last modified: 04 Mar 2021 02:36

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Contributors

Author: Daniel J. Asby
Author: Delphine Boche ORCID iD
Author: Stuart Allan
Author: Seth Love
Author: Scott Miners

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