engleski

Involvement of lymphatic and glymphatic systems in Alzheimer's disease.

While it is generally considered that stroke occursonly in the context of vascular disease, recent evidenceshows that all underlying processes leading to stroke depend on interactions of neurons, glial cells, vascular endothelial cells and pericytes, and components of the extracellular matrix, altogether referred to as a neurovascular unit, and that recovery after stroke also depends on the interaction of all structures within the neurovascular unit. Vascular disease and Alzheimer’sdisease (AD) have long been considered specific disease entities, mainly because the neuropathological changes that characterize AD are the deposition of amyloid β peptide (Aβ) in the brain parenchyma (amyloid or senile plaques, SP) and Aβ accumulation in the walls of cerebral arteries, arterioles, capillaries and veins (cerebral amyloid angiopathy, CAA), dysfunctions of the blood-brain barrier and the accumulation of neurofibrillary tangles (NFT) in neurons, whereas cerebrovascular disease can lead to vascular cognitive impairment (VCI) in different ways than AD. Most commonly, the underlying mechanism of stroke is ischemic (usually thrombotic, sometimes embolic, rarely due to systemic hypo-perfusion), and in about 15% of cases it is hemorrhagic (most often as intracerebral hemorrhage, and sometimes as subarachnoid hemorrhage). The currently prevailing opinion is that although AD and VCI can exist as separate entities, both conditions co-occur in as many as 60% of all patients with cognitive decline (Querfurthand Lafer, 2010). In one study, of all patients with a syndrome of dementia, 38% fulfilled the criteria for both AD and VaD, 30% had AD, 12% VaD, and the remaining 10% simultaneously met the criteria for AD and Lewy body disease or Parkinson’s disease and AD (Schneideret al., 2007). The prevalence of CAA in patients with AD varies from 70–100% (Tian et al., 2004), but more important is the fact that CAA in large blood vessels is characterized by the predominant deposition of Aβ1−40 and is usually not associated with AD but with VCI, while the disposal of the longer form (Aβ1−42) in pericapillary spaces (CapCAA) is highly associated with AD(Attems et al., 2004). These observations also support the claim that the main source of Aβ is neurons, Aβ being further drained through the interstitial fluid and deposited along the basement membrane of brain capillaries and larger blood vessels. It is well known thatthe longer form of the peptide (Aβ1−42) is strongly related to abnormal aggregation than the shorter form (Aβ1−40), and therefore its accumulation is considered a higher risk for the development of AD. I propose thata strong mechanism must exist in cerebral blood vessels that opposes clot formation as is the case in the periphery, to prevent stroke. Thus, prevention of microbleeds by Aβ might represent an evolutionary adaptation of the amyloid precursor protein (APP) anticoagulant function in the central nervous system to serve as a stroke-preventing agent. This is supported by the fact that APP is a soluble isoform of protease inhibitor nexin-2 (PN-2), as both of these proteins strongly inhibit coagulation factor XIa in peripheral blood, and by the fact that two out of five mutations in exons 16 and 17 of the APP gene, which encode part of the APP molecule from which later proteolytic cleavage by β-and γ-secretase will produce Aβ, cause fatal stroke in adulthood: the Flemish mutation (Cys692Gly) and the Italian mutation (Glu693Lys) ; however, two other mutations in the same region of the APP gene, are relatively less frequent and cause early AD: the Arctic mutation (Glu693Gly) and the Osaka mutation (Glu693Asp) (for review, see Šimić et al., 2017). By secretion from vascular endothelial cells in the brain and from neurons, PN-2 and Aβ could serve as preventative agents against stroke. As there is apparently no feedback signal or signalling pathway through which neurons receive the stop signal to cease creating Aβ by cleaving APP using the amyloidogenic pathway, neurons continue in AD to generate additional amounts of Aβ. Over time, the excess of Aβ precipitates and turns into insoluble aggregates, which further oligomerize and aggregate into insoluble fibrils in the form extracellular SP. In AD, this processis likely induced by reduced outflow of Aβ through the glymphatic system, which serves to clear molecules accumulating in the interstitial fluid. Recent data suggest that this process is principally dependent on the influx of water through aquaporin (AQP4) channels on astroglial processes that contribute to the blood-brain barrier. Other genetic, epigenetic, and microenvironmental factors are also involved. One of them could be leakage of divalent ions from plasma through a deficient blood-brain barrier into the neuropil. Divalent ions have been shown in vitro to accelerate the aggregation of Aβ. Until recently the central nervous system was considered to lack a system of lymphatic vessels that drains interstitial fluid and allows circulation of immunocompetent cells, but this view changed when lymphatic vessels where described in the mouse brain (Louveau et al., 2015). Most of these lymphatic vessels are aligned along the transverse and the upper sagittal sinuses, and contain cerebrospinal fluid (CSF), T lymphocytes, and dendritic cells. It was also demonstrated that these meningeal lymphatic vessels drain into the deep lymph nodes of the neck using Evan’s Blue (Louveau et al., 2015). Therefore, dysregulation or disruption of the blood-brain barrier and the glymphatic and lymphatic systems harbors the potential to contribute to the development of neurodegenerative diseases, particularly AD, and represent a potentially important and accessible target for the treatment of AD, and other neurodegenerative conditions.

Alzheimer's disease ; lymphatic system of the brain ; glymphatic system ; neurovascular unit ; amyloid precursor protein ; amyloid ; vascular cognitive impairment ; anticoagulant ; cerebral amyloid angiopathy ; protease inhibitor nexin 2

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