Moreover, evidence suggests that the BBB dysfunction is one of the most common pathophysiological hallmark of AD involved in vascular risk factors Tarasoff-Conway et al. De La Torre reviewed more than studies showing vascular involvement in AD. The leakage of substances from plasma into the CNS, changes in efflux and influx transporters leading to accumulation of the toxins in the CNS, and altered expression and secretion of proteins by the NVU cells are the critical pathways of vascular dysfunction connected with AD Deane and Zlokovic, ; Lok et al.
Thanks to the short distance between adjacent brain capillaries, a rapid exchange of substances between the CNS and blood circulation can occur. Malfunction of the nutrient and oxygen supply or impaired elimination of toxic metabolic waste can cause dysregulations of neuronal functioning. Activated NVU cells start to release pro-inflammatory cytokines and vasoactive substances.
Subsequent processes, such as the decrease of cerebral blood flow and amplification of cells, contribute to cognitive impairment. Zlokovic suggests that such physiological changes of the NVU, compromised brain microcirculation, and vascular neuroinflammatory responses play an important role in the development of AD Zlokovic, Moreover, in some AD brains, structural changes of the vasculature, such as increased numbers of fragmented vessels with fewer intact branches, atrophic string vessels, different irregularities in the capillary surface, changes of vessel diameter, thickening Zlokovic, , vacuolization Buee et al.
Increased numbers of pericytes Stewart et al. Pericytes work as gatekeepers of the BBB, and in cooperation with other NVU cells, they regulate the transport of nutrients and waste products between the interstitial fluid and peripheral blood Thomsen et al. Multiple studies implicate the connection between pericytes, BBB dysfunction, and neurologic diseases Machida et al. Endothelial cells of the BBB are strongly connected by tight junctions.
Yamazaki et al. Cerebrovascular inflammatory changes are associated with AD pathology. FTDP is clinically characterized by progressive behavioral, cognitive, and motor changes, including poor impulse control, inappropriate social conduct, apathy, worse cognitive control, and limited mental flexibility. These changes often precede the extrapyramidal and corticospinal motor signs and symptoms Sitek et al. Numerous cases of frontotemporal dementia show dynamic neuropathological changes caused by the abnormal deposition of protein tau Schweitzer et al.
FTDP is a subtype of frontotemporal dementia, and it represents a group of neurodegenerative tauopathies caused by mutations in tau and progranulin genes Hutton et al. There are some evidence about microvascular changes in frontotemporal dementia.
De Reuck et al. PSP is a 4R tauopathy characterized by progressive deterioration of brain cells, mostly in the region of the brainstem. Clinical features of RS include early gait instability, falls, supranuclear gaze palsy, axial rigidity, dysarthria, dysphagia, and progressive dementia.
PSP-P is clinically characterized by tremor, rigid bradykinesia, levodopa responsive, late cognitive decline, and longer life expectancy. The study characterizing the P - glycoprotein P-gp function at the BBB using [ 11 C]-verapamil PET in PSP patients revealed increased [ 11 C]-verapamil uptake in basal ganglia and frontal regions, suggesting decreased function of the transporter in these areas. Even if these results were not significant, they showed differences between the patients in various stages of the disease.
These results are consistent with regionally decreased P-gp function with the progression of the disease Bartels et al. This rare akinetic-rigid syndrome is characterized by asymmetric lower-body involvement, predominant corticospinal and pseudobulbar signs, urinary incontinence, cognitive impairment, increased frequency of stroke risk factors, and neuroimaging evidence of vascular changes in subcortical regions, especially the bilateral frontal lesions Lanza et al.
Vascular PSP differs from idiopathic PSP by a higher degree of asymmetry, lower body involvement, and evidence of corticospinal and pseudobulbar signs Winikates and Jankovic, CBD is a rare, progressive neurodegenerative 4R tauopathy associated with heterogeneous motor, sensory, behavioral, and cognitive symptoms. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons.
Tau pathology is extensively present in neurons and glial cells of the gray and white matter of the cortex, basal ganglia, diencephalon, and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, corticobasal syndrome, is characterized by asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus Kouri et al.
Moreover, the pathology of CBD can be associated with Richardson syndrome, behavioral variant of frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome Kouri et al. Recently, a few cases of vascular corticobasal syndrome CBS have been reported.
Koga et al. Multiple infarcts in the frontal lobe and motor cortex, periventricular white matter, thalamus, and basal ganglia were observed in two patients. One patient had no cortical infarct but had multiple white matter infarcts and corticospinal tract degeneration. This autopsy study showed that, while rare, cerebrovascular pathology can underlie clinical features suggestive of CBS Koga et al. In the past, CTE was referred to as dementia pugilistica.
The recent studies have shown neuropathological evidence of CTE in retired American football players, professional wrestlers, professional hockey or soccer players, as well as in nonathletes. CTE may have different causes, such as falls, motor vehicle accidents, assaults, epileptic seizures, or military combat Gavett et al. However, not all patients with repetitive brain trauma develop CTE, indicating that additional risk factors, including genetics, may play a role in the neuropathogenesis of this disease.
CTE is clinically manifested by impairments in cognition, behavior, and mood, and in some cases, chronic headache and motor and cerebellar dysfunction are occasionally accompanied by dizziness and headaches McKee et al.
Previous microvasculature studies of several dementia pugilistica cases revealed decreased microvascular density and tortuosity with a strong correlation between the laminar distribution of NFTs and pathological microvasculature. It has been suggested that repetitive head trauma may cause vascular damage with the subsequent NFTs and neuropil neurites formation in perivascular space McKee et al. A recent study proved the BBB disruption mainly in regions of intense perivascular tau deposition.
The accumulation of tau protein was associated with loss of the tight junction protein claudin-5 and enhanced extravasation of endogenous blood components such as fibrinogen and IgG Farrell et al. PDCG belongs to rare tauopathies. It is a disorder unique to the Chamorro people of Guam and the Mariana Islands. Strong familial clustering suggests the genetic origin of the disease Hirano et al. Parkinsonism, dementia, or a combination of both are found as initial symptoms; however, most PDC patients show a gait disturbance with additional extrapyramidal symptoms.
Patients with PDC shows recent memory deficits, disorientation in time and place, behavioral changes, and progressive deterioration of all intellectual skills. Over time, they reach a bedridden state Chen, Other clinical features include olfactory dysfunction and, in some individuals, oculomotor signs Kovacs, Neurofibrillary pathology similar to that observed in AD, but without the presence of amyloid plaques is found in most PDC cases Lee et al.
Previous studies described brain microvascular changes in PDC. They found a decrease in vascular density, atrophic, and fragmented microvessels with a reduced number of microvascular branches mainly in the areas affected by NFTs pathology Buee et al.
Recently, we showed that neurofibrillary pathology is closely associated with cerebrovascular inflammatory changes in Guam PDC patients. The areas with significant accumulation of the tau in the NFTs correlated with upregulation of adhesion molecules, disruption of tight junctions, morphological alterations in brain microvessels such as thickening of the vessel walls, and narrowing of the vessel lumens and an increase in collagen-type IV content per vessel Majerova et al.
Moreover, ramified astrocytes are present Komori, Severe neuronal and glial loss in PiD leads to frontotemporal lobe atrophy, and it is clinically manifested by the loss of verbal skills, personality changes, and progressive dementia Hardin and Schooley, ; Rohn et al.
Vascular changes in PiD, including thinning of microvessels, increased tortuosity, twisted vessels, and fragmentation of microvasculature. The structural changes of capillaries are comparatively severe as in AD Buee et al.
Massive disorganization of the laminar distribution of microvessels is shown mainly in atrophy-affected areas Buee et al. AGD is a highly frequent but still under-recognized neurodegenerative condition. AGD is a sporadic 4R tauopathy. In the past, AGD was reported as adult-onset dementia, but extended studies have revealed clinical features, such as changes of the personality, emotional imbalance, or memory problems.
Pathologically, AGD is characterized by the presence of spindle-shaped or comma-shaped argyrophilic grains in the neuropil of the entorhinal cortex, hippocampus, and amygdala Togo et al. GGTs represent a group of 4R tauopathies that are characterized neuropathologically by widespread globular glial inclusions. These tauopathies are very rare and they have a range of clinicopathological presentations. We can divide them into three main types—type I cases are typically presented with frontotemporal dementia correlating with the frontotemporal distribution of pathology, type II cases are predominately characterized by motor cortex and corticospinal tract degeneration, and type III cases can present with a combination of the frontotemporal, motor cortex, and corticospinal tract involvement.
Extrapyramidal features can be present in types II and III, and in all types of globular glial tauopathies, significant degeneration of the white matter can be observed Ahmed et al.
It is known that astrocytes play a key role in maintaining the BBB via astrocytic endfeet, which are directly opposed to vascular endothelial cells Ransom et al. Experiments on mice confirmed the mild BBB disruption after the targeted expression of human wild-type tau in murine astrocyte Zlokovic, ; Bartels et al. Aging-related tau astrogliopathy is characterized by the presence of two types of tau-bearing astrocytes.
The first type, thorn-shaped astrocytes, is located in the subependymal and subpial regions, perivascular spaces, and in clusters in the frontal and temporal cortices, basal forebrain, and brainstem. Both types can also be present in combination with other tauopathies Ferrer et al. The etiology of this disease remains unclear; however, functional changes of the BBB together with metabolic encephalopathy, neurodegenerative pathologies, aging-related hypoperfusion, AD, vascular dementia, and even repeated minor trauma with possible genetic risk factors may play a role Kovacs et al.
As discussed in previous sections, the neurofibrillary pathology is connected with changes at the neurovascular unit. Moreover, the distribution and load of neurofibrillary pathology is correlated with clinical phenotype and severity of cognitive impairment Nelson et al. Clinical studies suggest that the NVU changes may represent an early biomarker of human cognitive dysfunction Nation et al.
Montagne et al. However, major questions remain, such as how tau-induced NVU changes are presented at the clinical level and whether early biomarkers of these processes could help in more focused therapeutic intervention in the future. All authors read and approved the final draft of the manuscript. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Epilepsia 53, 45— Deane, R. Alzheimer Res. Desai, B. Cell Transplant. Di Liegro, I. Molecular Bases of Neurodegeneration. The tau protein is predominantly found in brain cells neurons. Tau is a small protein with a short name but a large reputation because of its association with multiple brain diseases. When mice are genetically designed to lack tau protein, their brain cells do not function properly, and tau dysfunction has been identified in a number of very severe human brain diseases.
Some other serious brain diseases associated with abnormal tau protein are chronic traumatic encephalopathy, Pick disease , frontotemporal dementia with parkinsonism FTDP , progressive supranuclear Palsy PSP , and corticobasal degeneration CBD.
Although each of these forms of dementia are different, they are all severe and progressive. The abnormal tau proteins found in these neurodegenerative diseases are not identical, although they are related. A genetically mutant form of tau can wreak havoc and does so in FTDP Then, after tau has been created from DNA, chemical activities in the brain further modify it in several ways. These chemical alterations of tau change its properties.
No longer fit to carry out its usual job, it takes on characteristics that are potentially very damaging. This form of tau no longer sticks together in the same way. The smaller forms of tau circulate among the neurons, interfering with cellular function. Tau phosphorylation at different sites has a different impact on its biological function and on its pathogenic role. The normal level of tau phosphorylation is a consequence of dynamic regulation of tau kinases and tau phosphatases.
Among the protein phosphatases, PP2A is known to be an important one. Despite extensive studies, the causes leading to abnormal hyperphosphorylation of tau are still not fully understood. The hyperphosphorylation of the tau protein reduces its binding affinity to microtubules, thus disrupting the structural organization and maintenance. Excess levels of unbound tau protein leads to the formation of tau aggregates, insoluble fibrils, and intracellular neurofibrillary tangles observed in Alzheimer's disease AD and other tauopathies.
In addition to hyperphosphorylation, alterations of tau itself, such as mutations in the MAPT gene, also plays a role in its aggregation. The isoforms of the tau proteins are the products of alternative splicing of exons 2, 3, and 10 of a single gene that in humans is known as MAPT Microtubule-Associated Protein Tau.
The six tau isoforms are designated as , , , , and They differ from each other by the presence or absence of one or two inserts N1, N2 in the N-terminal part, and by the presence of either three repeats R1, R3, R4 or four repeats R1, R2, R3 and R4 in the C-terminal part. The repeat domains, located in the C-terminus of Tau, are believed to be important for microtubule binding as well as for the aggregation of tau into paired helical filaments.
Tau, 43D Tau, AA Tau, Tau 12 Tau, TAU
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