The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.

Astrocyte–endothelial interactions at the blood–brain barrier

Structure and function of the blood–brain barrier

The neuropathological hallmarks of Alzheimer disease (AD) include “positive” lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and “negative” lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between “normal” aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.

/pdf/neuropathological-alterations-in-alzheimer-disease-2zexumi6x1.pdf

Neuropathological Alterations in Alzheimer Disease

Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.

Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.

The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of more than 20 degenerative conditions affecting either the central nervous system or a variety of peripheral tissues. As these conditions include Alzheimer's, Parkinson's and the prion diseases, several forms of fatal systemic amyloidosis, and at least one condition associated with medical intervention (haemodialysis), they are of enormous importance in the context of present-day human health and welfare. Much remains to be learned about the mechanism by which the proteins associated with these diseases aggregate and form amyloid structures, and how the latter affect the functions of the organs with which they are associated. A great deal of information concerning these diseases has emerged, however, during the past 5 years, much of it causing a number of fundamental assumptions about the amyloid diseases to be re-examined. For example, it is now apparent that the ability to form amyloid structures is not an unusual feature of the small number of proteins associated with these diseases but is instead a general property of polypeptide chains. It has also been found recently that aggregates of proteins not associated with amyloid diseases can impair the ability of cells to function to a similar extent as aggregates of proteins linked with specific neurodegenerative conditions. Moreover, the mature amyloid fibrils or plaques appear to be substantially less toxic than the pre-fibrillar aggregates that are their precursors. The toxicity of these early aggregates appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes, causing oxidative stress and increases in free Ca2+ that eventually lead to apoptotic or necrotic cell death. The 'new view' of these diseases also suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses. In addition, cellular protection mechanisms, such as molecular chaperones and the protein degradation machinery, appear to be crucial in the prevention of disease in normally functioning living organisms. It also suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.

http://virtuallaboratory.colorado.edu/Biofundamentals-2014/chapters/Protein%20Aggregation%20and%20toxicity.pdf

Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution

HLA-DRB1*14 and DQB1*05 are associated with Japanese anti-MuSK antibody-positive myasthenia gravis patients.

Inflammatory and immune responses are known to be involved in the pathogenesis of Alzheimer's disease (AD). NF-kappaB is a major transcription factor that plays a central role in the inflammatory and immune responses and is regulated by I-kappaB through an autoregulatory feedback system. Southwestern immunohistochemistry and immunohistochemistry in our study demonstrated activated NF-kappaB in AD brains. However, there was also activated expression of I-kappaB in a distribution that corresponded to the neurofibrillary pathology of AD. These observations indicate that disruption of the autoregulatory mechanism of NF-kappaB in brain regions with neurofibrillary pathology may play a role in the pathogenesis of AD.

Enhanced expression of I-κB with neurofibrillary pathology in Alzheimer's disease

Tufted astrocytes (TAs) are considered reliable, specific markers for the neuropathologic diagnosis of progressive supranuclear palsy (PSP). It is known that neurofibrillary tangles (NFTs) may relate directly to neurodegeneration, but the role of glial tau pathology is not well determined. To examine the hypothesis that TAs are as pathogenic as NFTs and that both might have a common accumulation, we evaluated the topographic relationship between TAs and NFTs in 12 cases of PSP. The sections of 13 different parts of the brain were stained using the Gallyas–Braak method, and TAs and NFTs were counted and compared statistically. The number of TAs significantly correlated with that of NFTs in the central gray matter, pontine nuclei, and tegmentum, which are responsible for the main symptoms in PSP. In the examined allocortex, however, NFTs were abundant without accompanying TAs. Staining with the specific antibody for 4-repeat tau (RD4) and 3-repeat tau (RD3) was performed to clarify this discrepancy from the standpoint of tau isoforms. NFTs in the entorhinal cortex were stained with both RD3 and RD4, but NFTs in the premotor cortex were stained with only RD4. The nature of NFTs in the allocortical area was different from that of the isocortex in PSP. TAs in the isocortex may share the same pathologic cascade with NFTs stained only by RD4. These results suggest that TAs are part of the same pathologic process as NFTs in PSP.

Astrocytic tau pathology positively correlates with neurofibrillary tangle density in progressive supranuclear palsy

Two patients with a condition clinically resembling juvenile muscular atrophy of distal upper extremity (Hirayama disease) showed forward protrusive movement of the posterior cervical dura matter during neck flexion. The dura displacement was characteristically limited in an approximately central portion of the posterior dura, which is different from Hirayama disease, which exhibits whole posterior dura displacement. Interestingly, the restricted dura in these patients showed thickening with reduced elastic fibers, indicating that the decreased stretchability of the posterior dura had caused motor dominant cervical myelopathy.

Flexion-induced cervical myelopathy associated with fewer elastic fibers and thickening in the posterior dura mater

We report a case of intravascular large B-cell lymphoma. A 52-year-old man gradually developed dementia and abnormal behaviors, which were later accompanied by spastic paraplegia and sensory disturbance in his lower limbs. MR imaging of his brain showed high signal intensity lesions on T2 imaging. IMP-SPECT images of the brain showed diffuse reduction of radioisotope uptake. Many skin rashes that looked like senile hemangioma were observed on his body. Several of those were biopsied, and the diagnosis of intravascular large B-cell lymphoma was made because of malignant B lymphocytes filling the vessel lumens in one of the seven biopsy specimens. CHOP therapy was performed and found to be effective for the neurological disorders such as dementia, paraplegia, and sensory disturbance. Our case suggests that skin biopsy for more than one sample of the skin rashes is very important for the diagnosis of intravascular large B-cell lymphoma. CHOP therapy might be effective in this case because of early diagnosis by skin biopsy.

Yasumasa Yoshiyama

Papers

HLA-DRB114 and DQB105 are associated with Japanese anti-MuSK antibody-positive myasthenia gravis patients.

Enhanced expression of I-κB with neurofibrillary pathology in Alzheimer's disease

Astrocytic tau pathology positively correlates with neurofibrillary tangle density in progressive supranuclear palsy

Flexion-induced cervical myelopathy associated with fewer elastic fibers and thickening in the posterior dura mater

[Beneficial effects of CHOP therapy in a case of intravascular large B-cell lymphoma diagnosed by skin biopsy].