Does the difference between PART and Alzheimer’s disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?

Weller, Roy O.; Hawkes, Cheryl A.; Carare, Roxana O.; Hardy, John

doi:10.1007/s00401-015-1416-1

Cited by 35 publications

(21 citation statements)

References 26 publications

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“…Interstitial fluid and solutes, including amyloid-β, are cleared from the grey matter through the PVD route, formed by two basement membranes in the walls of cerebral capillaries and arteries, into the cervical lymph nodes and systemic venous systems [9, 45, 46]. A congested PVD pathway could be one of the causes of CAA as amyloid-β distribution in CAA closely corresponds with the PVD route [73]. Soluble small molecules have a greater chance of being effectively cleared through the PVD route than large molecules [6].…”

Section: Discussionmentioning

confidence: 99%

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Saitô

Yamamoto

Maki

et al. 2017

acta neuropathol commun

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Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer’s disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-β proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-β and amyloid-β1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n = 5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n = 10–17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n = 4–6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n = 4–5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-β oligomer formation. In conclusion, taxifolin prevents amyloid-β oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.

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Section: Discussionmentioning

confidence: 99%

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Saitô

Yamamoto

Maki

et al. 2017

acta neuropathol commun

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“…As the route of drainage is within basement membranes [24], it is possible that the valve-like action results from changes in the orientation of the molecules within the basement membranes [122]. As vessels age, they become arteriosclerotic, stiff, and less elastic, particularly in humans, and such stiffening may interfere with perivascular drainage of ISF and soluble metabolites in elderly individuals [59, 139]. …”

Section: Lymphatic Drainage Of the Cnsmentioning

confidence: 99%

“…With age and Alzheimer’s disease, insoluble fibrillary Aβ is deposited in intramural basement membranes of capillaries and arteries of the brain as CAA. Age-related changes in cerebral arteries impair intramural perivascular drainage of ISF [54], and this may be a trigger for the amyloid cascade, loss of homeostasis and propagation of tau protein in the brain in Alzheimer’s disease [139]. …”

Section: Relationships Between Lymphatic Drainage Of the Brain And Nementioning

confidence: 99%

Vascular, glial, and lymphatic immune gateways of the central nervous system

et al. 2016

Self Cite

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Immune privilege of the central nervous system (CNS) has been ascribed to the presence of a blood–brain barrier and the lack of lymphatic vessels within the CNS parenchyma. However, immune reactions occur within the CNS and it is clear that the CNS has a unique relationship with the immune system. Recent developments in high-resolution imaging techniques have prompted a reassessment of the relationships between the CNS and the immune system. This review will take these developments into account in describing our present understanding of the anatomical connections of the CNS fluid drainage pathways towards regional lymph nodes and our current concept of immune cell trafficking into the CNS during immunosurveillance and neuroinflammation. Cerebrospinal fluid (CSF) and interstitial fluid are the two major components that drain from the CNS to regional lymph nodes. CSF drains via lymphatic vessels and appears to carry antigen-presenting cells. Interstitial fluid from the CNS parenchyma, on the other hand, drains to lymph nodes via narrow and restricted basement membrane pathways within the walls of cerebral capillaries and arteries that do not allow traffic of antigen-presenting cells. Lymphocytes targeting the CNS enter by a two-step process entailing receptor-mediated crossing of vascular endothelium and enzyme-mediated penetration of the glia limitans that covers the CNS. The contribution of the pathways into and out of the CNS as initiators or contributors to neurological disorders, such as multiple sclerosis and Alzheimer’s disease, will be discussed. Furthermore, we propose a clear nomenclature allowing improved precision when describing the CNS-specific communication pathways with the immune system.

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“…The ABCC9 genetic association may be a critical clue to help solve the riddle. Although there are valid reasons to contradistinguish neurodegenerative and cerebrovascular disorders, there is increasing evidence in support of a more nuanced paradigm with “mixed” pathogenetic mechanisms in the aged human brain (Montine, et al, 2014,Snyder, et al, 2014,Weller, et al, 2015). TDP-43 pathology is not specific for neurodegenerative diseases, having been reported in a wide variety of brain disorders including Alexander’s disease, Down syndrome, low-grade glial neoplasms, and chronic brain trauma (Davidson, et al, 2011,Lee, et al, 2008,Ling, et al, 2013,McKee, et al, 2010,Walker, et al, 2014), so there is overlap between pathologic findings that are seen in “reactive” and “neurodegenerative” conditions.…”

Section: Abcc9 In Hippocampal Sclerosis Of Aging (Hs-aging)mentioning

confidence: 99%

ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target

Nelson

Jicha

Wang

et al. 2015

Ageing Research Reviews

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The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“KATP”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a “druggable target”, relevant perhaps to both HS-Aging and Alzheimer’s disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.

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Does the difference between PART and Alzheimer’s disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?

Cited by 35 publications

References 26 publications

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

Vascular, glial, and lymphatic immune gateways of the central nervous system

ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target

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