The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: Therapeutic implications

The amyloid plaques in Alzheimer's disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Aβ depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Aβ deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while "later" neurodegenerative characteristics are not seen in these models. Next to the plaques, Aβ amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and medium-sized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed

Laser microdissection for spatial proteomics of postmortem brain tissue

Quantitative data of the proteome is highly valuable for providing unbiased information on protein expression changes related to disease or identifying related biomarkers. In brain diseases the affected area can be small and pathogenic events can be related to a specific cell type in an otherwise heterogeneous tissue type. An emerging approach dedicated to analysing this type of samples is laser microdissection (LMD) combined with LC-MS/MS into a single workflow. In this chapter, we describe two LMD methods for isolating tissue at the level of a small area and individual cells suitable for subsequent LC-MS/MS analysis

A laser microdissection–liquid chromatography–tandem mass spectrometry workflow for post-mortem analysis of brain tissue

Improved speed and sensitivity of mass spectrometry allow the simultaneous quantification of high numbers of proteins from increasingly smaller quantities of tissue sample. Quantitative data of the proteome is highly valuable for providing unbiased information on, for example, protein expression changes related to disease or identifying related biomarkers. In brain diseases the affected area can be small and pathogenic events can be related to a specific cell type in an otherwise heterogeneous tissue type. An emerging approach dedicated to analyzing this type of samples is laser micro-dissection (LMD) combined with LC-MS/MS into a single workflow. In this chapter, we describe different options for isolating tissue suitable for LC-MS/MS analysis

Laser microdissection for spatial proteomics of postmortem brain tissue

Quantitative data of the proteome is highly valuable for providing unbiased information on protein expression changes related to disease or identifying related biomarkers. In brain diseases the affected area can be small and pathogenic events can be related to a specific cell type in an otherwise heterogeneous tissue type. An emerging approach dedicated to analysing this type of samples is laser microdissection (LMD) combined with LC-MS/MS into a single workflow. In this chapter, we describe two LMD methods for isolating tissue at the level of a small area and individual cells suitable for subsequent LC-MS/MS analysis

The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E2 secretion by cultured human adult microglia: Implications for Alzheimer's disease

Microglial cyclo-oxygenase (COX) expression is considered to be important in the pathogenesis of Alzheimer's disease (AD) and, therefore, constitutes a key target for therapeutic intervention. We investigated the influence of AD plaque associated factors on COX-1 and COX-2 expression and activity in adult human microglial cells in vitro. COX-2 immunoreactivity and mRNA were induced by lipopolysaccharide (LPS), not by AD plaque associated cytokines interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor (TNF)-α, or amyloid (A)β1-42. To assess functional COX activity, the release of PGE2 into the culture medium was determined. LPS and also arachidonic acid (AA) dose-dependently stimulated PGE2 release. The effects of AA are independent from induction of COX mRNA expression, or of de novo protein synthesis. No effects of either plaque-associated cytokines or Aβ1-42 on PGE2 secretion were seen, even when cells were co-stimulated with AA, to provide enough substrate. COX isotype selective inhibitors were used to discern relative contributions of COX-1 and COX-2 activities to microglial PGE2 secretion. COX-2 and in part COX-1-selective inhibitors inhibited LPS-induced PGE2 secretion, whereas the AA-induced PGE2 secretion was reduced by COX-1-selective inhibitors only. Apparently, adult human microglia in vitro (1) constitutively express COX-1, and (2) do not express COX-2 upon exposure to either Aβ or plaque associated cytokines. In the light of microglial COX activity as a potential therapeutical target in AD, the data presented in this study suggest that classical NSAIDs, rather than selective COX-2 inhibitors, are more potent in reducing microglial prostaglandin secretion

Cerebrospinal Fluid Amyloid-beta Subtypes in Confirmed Frontotemporal Lobar Degeneration Cases: A Pilot Study : A Pilot Study

To investigate amyloid-β (Aβ) in frontotemporal dementia (FTD), cerebrospinal fluid (CSF) Aβ38, Aβ40, and Aβ42 in frontotemporal lobar degeneration (FTLD; N = 18 genetically and/or pathologically confirmed and N = 8 FTD with concomitant amyotrophic lateral sclerosis) were compared with Alzheimer's disease (AD; pathological or Pittsburgh-compound-B Positron-emission-tomography (PIB-PET) positive; N = 25) and controls (N = 24). For all the Aβ subtypes, group difference was seen and post-hoc analysis revealed lower levels in FTLD compared to controls (p≤0.05). Aβ42/40 ratio showed no difference between FTLD and controls; however, a difference was seen between AD versus FTLD (p < 0.01). This is an intriguing finding, suggesting a possible role of Aβ in FTLD pathogenesis

The spectrum of MR detectable cortical microinfarcts: A classification study with 7-tesla postmortem MRI and histopathology

Cerebral microinfarcts (CMIs) are common neuropathologic findings in aging and dementia. We explored the spectrum of cortical CMIs that can be visualized with 7T magnetic resonance imaging (MRI). Thirty-three coronal brain slices of 11 individuals with neuropathologically confirmed dementia were subjected to a high-resolution postmortem 7T MRI protocol. First, we identified all visible small (≤5 mm) intracortical and juxtacortical lesions on postmortem MRI. Lesions were classified as CMI or nonCMI based on histology, and their MR features were recorded. Thirty lesions were identified on the initial MRI evaluation, of which twenty-three could be matched with histology. Histopathology classified 12 lesions as CMIs, all of which were located intracortically. On the basis of their MR features, they could be classified as chronic gliotic CMIs - with or without cavitation or hemorrhagic components - and acute CMIs. Eleven MRI identified lesions were not of ischemic nature and most commonly enlarged or atypically shaped perivascular spaces. Their MRI features were similar to gliotic CMIs with or without cavitation, but these 'CMI mimics' were always located juxtacortically. 7T postmortem MRI distinguishes different histopathologic types of cortical CMIs, with distinctive MR characteristics. On the basis of our findings, we propose in vivo rating criteria for the detection of intracortical CMIs

Amyloid βprotein precursor in cultured leptomeningeal smooth muscle cells

Smooth muscle cell cultures were established from human leptomeningeal blood vessels obtained at autopsy from a patient with normal cortical blood vessels and a patient with extensive cerebral amyloid angiopathy (CAA). The normal leptomeningeal smooth muscle cells and CAA/ leptomeningeal smooth muscle cells were compared to normal human aorta smooth muscle cells with respect to amyloid βprotein precursor (AβPP) expression. All the cultured smooth muscle cells secreted a prominent =110 kDaform of AβPP that contained the Kunitz-type serine protease inhibitor domain analogous to protease nexin-2 (PN-2). Quantitative measurements revealed that aorta smooth muscle cells secrete -1.5-fold more PN-2/ABPP than normal leptomeningeal smooth muscle cells and CAA/ leptomeningeal smooth muscle cells. In contrast, the normal leptomeningeal smooth muscle cells and CAA/ leptomeningeal smooth muscle cells retain =2.4- and =3.3-fold, respectively, more cell-associated AβPP than aorta smooth muscle cells. These preliminary findings suggest that the decreased secretion of PN-2/AβPP observed in leptomeningeal smooth muscle cells compared to aorta smooth muscle cells may contribute to the formation of Aβ that is selectively deposited in the walls of cortical and leptomeningeal blood vessels

The neuropathology of gluten-related neurological disorders: A systematic review

Gluten-related neurological disorders (GRND) represent a spectrum of neurological manifestations that are triggered by gluten. In coeliac disease, a T-cell mediated enteropathy is triggered by gluten in genetically predisposed individuals. The underlying pathological mechanism of the neurological dysfunction is not yet clear. The aim of this review is to collate existing neuropathological findings in GRND as a means of aiding the understanding of the pathophysiology. A systematic search of the Pubmed Database yielded 188 articles, of which 32 were included, containing 98 eligible cases with a description of pathological findings in GRND. In gluten ataxia, loss of Purkinje cells, atrophy, gliosis and astrocytosis were apparent, as well as diffuse lymphocytic infiltration and perivascular cuffing with lymphocytes. In patients with large-fiber neuropathy, nerve biopsies revealed axonopathy, loss of myelinated fibers and focal and perivascular infiltration by inflammatory cells. Inflammatory infiltrate was also observed in muscle in myopathy and in cerebrum of patients with encephalopathy and patients with epilepsy. Such changes were not seen in skin biopsies from patients with small fiber neuropathies. The findings from this systematic review suggest an immune mediated pathogenesis for GRND. Future research should focus on the characterization of the inflammatory cell infiltrates and identifying target epitopes

Association of vascular amyloid β and cells of the mononuclear phagocyte system in hereditary cerebral hemorrhage with amyloidosis (Dutch) and Alzheimer disease

Arterial and arteriolar amyloid-β (Aβ) deposition in hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) and Alzheimer disease (AD) cerebral amyloid angiopathy (CAA) were studied as to morphology, extent, and association with mononuclear phagocyte system (MPS) cells using Aβ, a- smooth muscle actin, and monocyte/macrophage marker (HLA-DR, CD68, CD11c, CD45) immunohistochemistry. The HCHWA-D/AD arterial/arteriolar media showed compact Aβ deposits, first appearing at the media/adventitia junction, and concomitant smooth muscle loss. Only HCHWA-D CAA featured (a) severe involvement of larger arteries and (b) arterioles showing a single or double ring of radial Aβ surrounding compact Aβ. Radial Aβ appeared to develop at the media/adventitia junction. Monocyte/macrophage marker-positive foci/cells co-localized with HCHWA-D arterial Aβ. Focal HLA-DR/CD11c positivity was observed at the media/adventitia junction of AD/HCHWA-D arteries in the absence of local Aβ, but not in controls. Monocyte/macrophage marker positivity co-localizing with radial Aβ appeared continuous with perivascular cells and microglia clustering perivascularly. These results suggest that (a) MPS cells are topographically associated with HCHWA-D arterial Aβ and radial arteriolar Aβ, and (b) HLA-DR/CD11c immunoreactivity may appear at the media/adventitia junction prior to Aβ. The latter finding and the assumed formation of radial Aβ at the media/adventitia junction may relate to involvement of the abluminal basement membrane in CAA pathogenesis. The role of MPS cells in this process remains to be established