Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease

Liu, Chia-Chen; Yu, Yun William; Heckman, Michael G.; Martens, Yuka A.; Ji, Lin; Yamazaki, Akari; Diehl, Nancy N.; Zhao, Jing; Zhao, Na; DeTure, Michael; Davis, Mary Dabney; Felton, Lindsey M.; Qiao, Wenhui; Li, Yonghe; Li, Hongmei; Fu, Yuan; Wang, Na; Wren, M. W. D.; Aikawa, Tomonori; Holm, Magnus; Oue, Hiroshi; Linares, Cynthia; Allen, Mariet; Carrasquillo, Minerva M.; Murray, Melissa E.; Petersen, Ronald C.; Ertekin-Taner, Nilüfer; Dickson, Dennis W.; Kanekiyo, Takahisa; Bu, Guojun

doi:10.1002/alz.12104

Cited by 46 publications

(66 citation statements)

References 60 publications

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“…With the increase in age, the aging scores in both disease and normal aged individuals showed an upward trend. The results also showed that the accelerated aging pattern in ND compared with the normal aged people, which was consistent with previous studies ( Liu et al, 2020 ). Compared with the chronological age, the aging score was more informative.…”

Section: Resultssupporting

confidence: 93%

Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain

Shi

Chen

et al. 2021

Front. Genet.

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Background: Neurodegenerative Diseases (NDs) are age-dependent and include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and so on. There have been numerous studies showing that accelerated aging is closely related (even the driver of) ND, thus promoting imbalances in cellular homeostasis. However, the mechanisms of how different ND types are related/triggered by advanced aging are still unclear. Therefore, there is an urgent need to explore the potential markers/mechanisms of different ND types based on aging acceleration at a system level.Methods: AD, PD, PSP, FTD, and aging markers were identified by supervised machine learning methods. The aging acceleration differential networks were constructed based on the aging score. Both the enrichment analysis and sensitivity analysis were carried out to investigate both common and specific mechanisms among different ND types in the context of aging acceleration.Results: The extracellular fluid, cellular metabolisms, and inflammatory response were identified as the common driving factors of cellular homeostasis imbalances during the accelerated aging process. In addition, Ca ion imbalance, abnormal protein depositions, DNA damage, and cytoplasmic DNA in macrophages were also revealed to be special mechanisms that further promote AD, PD, PSP, and FTD, respectively.Conclusion: The accelerated epigenetic aging mechanisms of different ND types were integrated and compared through our computational pipeline.

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Section: Resultssupporting

confidence: 93%

Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain

Shi

Chen

et al. 2021

Front. Genet.

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“…Several experimental studies have shown that modelling of cerebral hypoperfusion increases tau phosphorylation: in adult Wistar rats [108], transgenic mice with Aβ and tau accumulation [109], and rat and human brain slices exposed to oxygen and glucose deprivation [110]. In a recent autopsy study, elevated levels of soluble tau and insoluble phosphotau were associated with lower levels of endothelial tight junction proteins, claudin-5 and occludin, in AD [111]. Tau-overexpressing mice were shown to have abnormal blood vessel morphology and increased vessel density [112].…”

Section: The Types Of Cerebral Ischaemic Damage Seen In Covid-19 Are mentioning

confidence: 99%

Cognitive impact of COVID-19: looking beyond the short term

2020

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COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence of central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It is unclear how much of the ischaemic damage is mediated by direct or inflammatory effects of virus on the CNS vasculature and how much is secondary to extracranial cardiorespiratory disease. Limited data suggest that the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibres, or by haematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons. Extracranially, SARS-CoV-2 targets endothelial cells and pericytes, causing endothelial cell dysfunction, vascular leakage and immune activation, sometimes leading to disseminated intravascular coagulation. It remains to be confirmed whether endothelial cells and pericytes in the cerebral vasculature are similarly targeted. Several aspects of COVID-19 are likely to impact on cognition. Cerebral white matter is particularly vulnerable to ischaemic damage in COVID-19 and is also critically important for cognitive function. There is accumulating evidence that cerebral hypoperfusion accelerates amyloid-β (Aβ) accumulation and is linked to tau and TDP-43 pathology, and by inducing phosphorylation of α-synuclein at serine-129, ischaemia may also increase the risk of development of Lewy body disease. Current therapies for COVID-19 are understandably focused on supporting respiratory function, preventing thrombosis and reducing immune activation. Since angiotensin-converting enzyme (ACE)-2 is a receptor for SARS-CoV-2, and ACE inhibitors and angiotensin receptor blockers are predicted to increase ACE-2 expression, it was initially feared that their use might exacerbate COVID-19. Recent meta-analyses have instead suggested that these medications are protective. This is perhaps because SARS-CoV-2 entry may deplete ACE-2, tipping the balance towards angiotensin II-ACE-1-mediated classical RAS activation: exacerbating hypoperfusion and promoting inflammation. It may be relevant that APOE ε4 individuals, who seem to be at increased risk of COVID-19, also have lowest ACE-2 activity. COVID-19 is likely to leave an unexpected legacy of long-term neurological complications in a significant number of survivors. Cognitive follow-up of COVID-19 patients will be important, especially in patients who develop cerebrovascular and neurological complications during the acute illness.

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“…CBF reduction is a typical phenotype in AD patients and relates to cognitive decline [ 71 ]. In addition, tau is associated with TJ proteins reduction in the cortical region of AD brains [ 72 ]. According to these studies, it is clear that tau/NFT induces blood vessels morphology changes and vascular dysfunction.…”

Section: Blood–brain Barrier Dysfunction In Neurodegenerative Diseasesmentioning

confidence: 99%

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

Sonninen

Peltonen

et al. 2021

IJMS

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The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

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Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer's disease

Cited by 46 publications

References 60 publications

Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain

Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain

Cognitive impact of COVID-19: looking beyond the short term

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

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