Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration

Park, Laibaik; Hochrainer, Karin; Hattori, Yorito; Ahn, Sung Ji; Anfray, Antoine; Wang, Gang; Uekawa, Ken; Seo, James; Palfini, Victoria; Blanco, Ismary; Acosta, Diana; Eliezer, David; Zhou, Ping; Anrather, Josef; Iadecola, Costantino

doi:10.1038/s41593-020-0686-7

Cited by 100 publications

(146 citation statements)

References 64 publications

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“…Recording of CBF and vascular reactivity. As in previous studies by us and others (Park et al, 2008a(Park et al, , 2014(Park et al, , 2020Tong et al, 2012), we used the cerebral cortex to investigate the role of tPA in the neurovascular dysfunction of Ab . We studied the neocortex because (1) it is easily accessible for experimental manipulations and dynamic measurement of CBF and (2) neurovascular uncoupling is also observed in the cerebral cortex of patients with AD (Mentis et al, 1998;Smith et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

et al. 2020

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The amyloid-b (Ab) peptide, a key pathogenic factor in Alzheimer's disease, attenuates the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a vital homeostatic response in which NMDA receptors (NMDARs) play a role through nitric oxide, and the CBF increase produced by endothelial factors. Tissue plasminogen activator (tPA), which is reduced in Alzheimer's disease and in mouse models of Ab accumulation, is required for the full expression of the NMDAR-dependent component of functional hyperemia. Therefore, we investigated whether tPA is involved in the neurovascular dysfunction of Ab. tPA activity was reduced, and the tPA inhibitor plasminogen inhibitor-1 (PAI-1) was increased in male mice expressing the Swedish mutation of the amyloid precursor protein (tg2576). Counteracting the tPA reduction with exogenous tPA or with pharmacological inhibition or genetic deletion of PAI-1 completely reversed the attenuation of the CBF increase evoked by whisker stimulation but did not ameliorate the response to the endothelium-dependent vasodilator acetylcholine. The tPA deficit attenuated functional hyperemia by suppressing NMDAR-dependent nitric oxide production during neural activity. Pharmacological inhibition of PAI-1 increased tPA activity, prevented neurovascular uncoupling, and ameliorated cognition in 11-to 12-month-old tg2576 mice, effects associated with a reduction of cerebral amyloid angiopathy but not amyloid plaques. The data unveil a selective role of the tPA in the suppression of functional hyperemia induced by Ab and in the mechanisms of cerebral amyloid angiopathy, and support the possibility that modulation of the PAI-1-tPA pathway may be beneficial in diseases associated with amyloid accumulation. Significance StatementAmyloid-b (Ab ) peptides have profound neurovascular effects that may contribute to cognitive impairment in Alzheimer's disease. We found that Ab attenuates the increases in blood flow evoked by neural activation through a reduction in tissue plasminogen activator (tPA) caused by upregulation of its endogenous inhibitor plasminogen inhibitor-1 (PAI-1). tPA deficiency prevents NMDA receptors from triggering nitric oxide production, thereby attenuating the flow increase evoked by neural activity. PAI-1 inhibition restores tPA activity, rescues neurovascular coupling, reduces amyloid deposition around blood vessels, and improves cognition in a mouse model of Ab accumulation. The findings demonstrate a previously unappreciated role of tPA in Ab -related neurovascular dysfunction and in vascular amyloid deposition. Restoration of tPA activity could be of therapeutic value in diseases associated with amyloid accumulation.

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Section: Methodsmentioning

confidence: 99%

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

et al. 2020

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“…Indeed, chronic in ammation is known to pose a risk for cardiovascular health which with aging may contribute to overlapping pathologies (Metti and Cauley 2012;Newcombe et al 2018). This is further supported by recent evidence indicating that hyperphosphorylated Tau can cause neurovascular decoupling (Park et al 2020) bridging characteristic AD-mechanisms to vascular de cits. Another important limitation of the current study is that we have not examined such anatomical or biochemical differences by sex as only male animals were included in this study.…”

Section: Resultsmentioning

confidence: 74%

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Bathini

Dupanloup

Zenaro

et al. 2021

Preprint

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Background Alzheimer's disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, and non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form of the disease. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and stress such as viral or bacterial infection causing chronic inflammation are underlying culprits of neurodegenerative dementia. Dementias that share or mimic pathological processes of AD include cerebrovascular diseases, Lewy body disease, TDP-43 proteinopathy. To date, very few mouse models reproduce the pathophysiological progression of mixed-vascular-AD, while the majority of studies have employed transgenic animals reproducing the familial form. Methods We have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL), in parallel to Vascular dementia (VaD) patients’ specimens.Results We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows a reproducibility of some gene targets in vascular dementia specimens rather than AD ones.Conclusions The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-VaD-AD phenotype, with progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling and the loss of neuronal functionality seen to some extent in humans.

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“…Here Park et al 2 show that tau, too, may play a critical role in dementia by impairing vascular function in early stages of the disease, before irreversible neuronal damage has occurred.…”

Section: Pathological Tau Disrupts the Association Between Nitric Oxide (No) Synthase And Psd95 Impairing No Signalling And Neurovascularmentioning

confidence: 97%

First, tau causes NO problem

Bonnar

Hall

2020

Nat Neurosci

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Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration

Cited by 100 publications

References 64 publications

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

First, tau causes NO problem

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