Alzheimer's disease: mismatch between amyloid plaques and neuritic plaques

Isocortical amyloid deposits and neurofibrillary changes were studied using selective silver staining methods. Amyloid was found in plaque-like formations varying in size and shape. The distribution pattern of these plaques as seen in the silver-stained preparations was identical to that recognized by A4 protein (amyloid) immunostaining. Consecutive sections stained for amyloid and neurofibrillary changes revealed the absence of intraneuronal cytoskeleton abnormalities within the boundaries of many of the amyloid plaques. Congo red preparations did not show these plaques and the tissue within the range of the plaques did not reveal any conspicuous neuropil distortions and/or glial cell accumulations. Hence, a considerable proportion of the amyloid plaques do not correspond to and should carefully be distinguished from 'primitive', 'mature', and 'burned out' types of neuritic (senile) plaques.     

Interleukin-8 receptor B immunoreactivity in brain and neuritic plaques of Alzheimer's disease.

Cytokines mediate inflammatory responses through their receptors in the hematopoietic system. In a search for potential mediators of inflammatory responses in Alzheimer's disease, we examined brain for cytokine receptors. Herein we describe interleukin-8 receptor B (IL-8RB, also termed CXCR2) immunoreactivity in the central nervous system. Strong IL-8RB immunoreactivity is present in both Alzheimer's disease and control brains. Neurons, dendrites, and axons are clearly immunoreactive. In Alzheimer's disease, IL-8RB immunoreactivity is also present in some swollen dystrophic neurites of neuritic plaques. Double staining and confocal microscopic analysis reveals that these IL-8RB-positive neurites in plaques are neurofilament positive and are distinct from astrocytic or microglial processes. In general, these IL-8RB-positive neurities do not co-localize with PHF-1 or AT8 (hyperphosphorylated tau) immunoreactive neurites but instead co-localize with beta PP-positive neurites. These results demonstrate for the first time IL-8RB immunoreactivity in the central nervous system and imply a new role for this receptor outside the hematopoietic system. The strong presence of IL-8RB on neurons and the potential of glial cells to produce IL-8 suggest that this system might mediate neuronal-glial interactions.     

Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease

All our advanced, severe cases of Alzheimer's disease have dramatic cholinergic cell losses in the nucleus basalis of Meynert even after correction for cell or nucleoli shrinkage. There is a good correlation between choline acetyltransferase activity and "healthy" cell number in the nucleus basalis of Meynert. Half of the Alzheimer disease cases have markedly reduced cortical choline acetyltransferase activity in spite of preserved nucleus basalis of Meynert choline acetyltransferase activity, suggesting a deficiency of cortical origin and/or of axonal transport in Alzheimer disease. The relationship between cell loss in the various sub-divisions of the nucleus basalis of Meynert and plaque counts in corresponding and non-corresponding projection areas of the cortex has also been examined. Globally, this relation appears more obvious when cell loss in a sub-division of the nucleus basalis of Meynert is compared to plaque counts in its cortical projection area. However, the relation is discontinuous with few or no data to document the intermediary stages of the process, probably reflecting the severity of our Alzheimer disease cases.     

Perivascular neuritic dystrophy associated with cerebral amyloid angiopathy in Alzheimer's disease

Cerebral amyloid angiopathy (CAA) affects both leptomeningeal and parenchymal blood vessels and is common in Alzheimer's disease (AD). In some vessels, CAA is accompanied by localized neuritic dystrophy around the affected blood vessel. The aim of this study was to assess the distribution and severity of perivascular neuritic dystrophy in primary visual and visual association cortices. The severity of perivascular neuritic dystrophy and Abeta deposition was scored in an association cortex (Brodmann area 18) and a primary cortex (Brodmann area 17) with double labeling immunohistochemistry for tau and Abeta in 31 cases of AD with severe CAA. The perivascular tau neuritic dystrophy score was significantly worse in visual association cortex than in primary visual cortex. On the other hand, there was no difference in the perivascular Abeta score between the two cortices. There were positive correlations between the severity of perivascular tau and perivascular Abeta scores for both primary and association cortices. The results suggest that the local neuronal environment determines the severity and nature of the perivascular neuritic pathology more than the severity of the intrinsic vascular disease and suggest a close association between perivascular amyloid deposits, so-called dyshoric angiopathy, and perivascular neuritic dystrophy.     

Substance P and somatostatin coexist within neuritic plaques: implications for the pathogenesis of Alzheimer's disease

In recent years the present authors and others have sought to determine the neurochemical composition of the dilated neuronal processes found within neuritic plaques of patients with Alzheimer's disease. To date a number of neurotransmitter and neuropeptide systems have been observed within different plaques, yet at present it is unclear whether individual human plaques contain more than one transmitter substance. In the present study a highly sensitive dual-immunolabeling procedure was employed and it was demonstrated that substance P and somatostatin-immunoreactive profiles coexist within single senile plaques of patients with Alzheimer's disease. Coexistence of somatostatin and substance P immunoreactivity within plaques was observed in the hippocampus and amygdala but not in the neocortex, although the latter region contained plaques within which somatostatin and substance P existed alone. The frequency with which we observed one or more neuropeptide within plaques was relatively low and in fact most plaques contained neither substance P nor somatostatin immunoreactivity. In addition, a large number of swollen peptidergic processes were observed outside of plaques. The significance of these observations with respect to the pathogenesis of Alzheimer's disease is discussed.     

Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease

Previously, we have shown that caspase-6 but not caspase-3 is activated by serum deprivation and induces a protracted cell death in primary cultures of human neurons (LeBlanc AC, Liu H, Goodyer C, Bergeron C, Hammond J: Caspase-6 role in apoptosis of human neurons, amyloidogenesis and Alzheimer's disease. J Biol Chem 1999, 274:23426-23436 and Zhang Y, Goodyer C, LeBlanc A: Selective and protracted apoptosis in human primary neurons microinjected with active caspase-3, -6, -7, and -8. J Neurosci 2000, 20:8384-8389). Here, we show with neoepitope antibodies that the p20 subunit of active caspase-6 increases twofold to threefold in the affected temporal and frontal cortex but not in the unaffected cerebellum of Alzheimer's disease brains and is present in neurofibrillary tangles, neuropil threads, and the neuritic plaques. Furthermore, a neoepitope antibody to caspase-6-cleaved Tau strongly detects intracellular tangles, extracellular tangles, pretangles, neuropil threads, and neuritic plaques. Immunoreactivity with both antibodies in pretangles indicates that the caspase-6 is active early in the pathogenesis of Alzheimer's disease. In contrast to the nuclear and cytosolic localization of active caspase-6 in apoptotic neurons of fetal and adult ischemic brains, the active caspase-6 in Alzheimer's disease brains is sequestered into the tangles or neurites. The localization of active caspase-6 may strongly jeopardize the structural integrity of the neuronal cytoskeletal system leading to inescapable neuronal dysfunction and eventual cell death in Alzheimer's disease neurons. Our results suggest that active caspase-6 is strongly implicated in human neuronal degeneration and apoptosis.     

Role of neuritic plaques and blood brain barrier in pathogenesis of Alzheimer''s disease

The authors suggest primary roles for the neuritic plaque and a breakdown in the blood brain barrier in Alzheimer's disease. Although the role of the plaque seems reasonable and empirically justified, the hypothesized role for changes in the blood brain barrier remains in doubt.     

The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer''s disease.

Two immunocytochemical probes were used to specifically identify and localize heparan sulphate proteoglycans (HSPGs) in 17 cases of Alzheimer's disease (AD). A monoclonal (HK-102) and an affinity-purified polyclonal antibody, each recognizing specific domains on the protein core of a basement membrane-derived HSPG, localized HSPGs to the amyloid fibrils present in neuritic plaques (NPs) and congophilic angiopathy (CA) in the brains of Alzheimer's patients, with weak to no immunostaining in neurofibrillary tangles from the same tissues. HSPGs were also demonstrated in "primitive plaques," suggesting that their accumulation takes place during early stages of plaque development. Immunolocalization of HSPGs to subsets of astrocytes and neuronal cells, particularly those in close proximity to NPs and CA, suggested possible involvement of these two cell types in deposition of HS-PGs into the amyloidotic lesions. The current study not only identifies a new component (HSPGs) present in the amyloid deposits of NPs and CA but also suggests that astrocytes, neurons, or both may be involved in its deposition at these sites.     

Siglec receptors and hiding plaques in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease. One hallmark of this disease is the continuous increase in the numbers and size of aggregating amyloid plaques. The accumulation of extracellular plaques is an immunologically interesting phenomenon since microglial cells, brain-specific macrophages, should be able to cleanse the aggregating material from the human brain. Immunotherapy targeting β-amyloid peptides in plaques with antibodies represents a promising therapy in AD. Recent progress in pattern recognition receptors of monocytes and macrophages has revealed that the sialic acid-binding, immunoglobulin-like lectin (Siglec) family of receptors is an important recognition receptor for sialylated glycoproteins and glycolipids. Interestingly, recent studies have revealed that microglial cells contain only one type of Siglec receptors, Siglec-11, which mediates immunosuppressive signals and thus inhibits the function of other microglial pattern recognition receptors, such as TLRs, NLRs, and RAGE receptors. We will review here the recent literature which clearly indicates that aggregating amyloid plaques are masked in AD by sialylated glycoproteins and gangliosides. Sialylation and glycosylation of plaques, mimicking the cell surface glycocalyx, can activate the immunosuppressive Siglec-11 receptors, as well as hiding the neuritic plaques, allowing them to evade the immune surveillance of microglial cells. This kind of immune evasion can prevent the microglial cleansing process of aggregating amyloid plaques in AD.     

阿尔茨海默病老年斑相关研究进展

正阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性痴呆为特征的年龄相关性神经退行性疾病,老年斑(senile plaques,SP)为其典型病理特征之一~([1-2])。随着世界范围内老龄化社会的到来,AD发病率呈逐年递增趋势。来自世界卫生组织的报道称,目前全世界范围内该病患者高达3 560万,每20年患病人数将翻一番,预计2050年可达到1.154亿人~([3]),这一疾病正在成为国际神经疾病研究的热点。1907年,德国神经病理学     

Neuroinflammatory phenotype in early Alzheimer's disease

Alzheimer's disease (AD) involves progressive neurodegeneration in the presence of misfolded proteins and poorly-understood inflammatory changes. However, research has shown that AD is genetically, clinically, and pathologically heterogeneous. In frozen brain samples of frontal cortex (diseased) and cerebellum (nondiseased) from the University of Kentucky Alzheimer's Disease Center autopsy cohort, we performed gene expression analysis for genes categorizing inflammatory states (termed M1 and M2) from early and late stage AD, and age-matched nondemented controls. We performed analysis of the serum samples for a profile of inflammatory proteins and examined the neuropathologic data on these samples. Striking heterogeneity was found in early AD. Specifically, early-stage AD brain samples indicated apparent polarization toward either the M1 or M2 brain inflammatory states when compared with age-matched nondisease control tissue. This polarization was observed in the frontal cortex and not in cerebellar tissue. We were able to detect differences in AD neuropathology, and changes in serum proteins that distinguished the individuals with apparent M1 versus M2 brain inflammatory polarization.     

Choline acetyltransferase immunoreactivity in neuritic plaques of Alzheimer brain

We have observed dystrophic choline acetyltransferase (ChAT)-positive processes surrounding the amyloid core of neuritic plaques in human neocortex, amygdala and hippocampus, using a polyclonal anti-human ChAT antiserum. These data, and those from studies of the aged monkey by other investigators, provide a morphologic counterpart for the biochemical abnormality of the cholinergic system in Alzheimer's disease and senile dementia of the Alzheimer type.     

Saccharides of senile plaques and neurofibrillary tangles in Alzheimer's disease

The contribution that oligosaccharides might make to the structure of the senile plaque and the neurofibrillary tangle was investigated using lectin histochemistry in 9 patients with Alzheimer's disease. One group of 4 lectins diffusely stained the neurites of senile plaques whereas two groups of 6 different lectins stained neurofibrillary tangles within neuronal perikarya and plaque neurites. Neuraminidase pretreatment abolished staining of tangles by one of these latter groups, but did not affect staining by the other group. Senile plaque core amyloid failed to stain with any lectin. It is concluded that oligosaccharides may contribute, but in different ways, to glycoprotein or glycolipid residues that form an integral part of the structure of the senile plaque and the neurofibrillary tangle.     

Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease

Plaques are a defining neuropathological hallmark of Alzheimer's disease (AD) and the major constituent of plaques, the beta-amyloid peptide (Abeta), is considered to play an important role in the pathophysiology of AD. But the biological origin of Abeta plaques and the mechanism whereby Abeta is involved in pathogenesis have been unknown. Abeta plaques were thought to form from the gradual accumulation and aggregation of secreted Abeta in the extracellular space. More recently, the accumulation of Abeta has been demonstrated to occur within neurons with AD pathogenesis. Moreover, intraneuronal Abeta accumulation has been reported to be critical in the synaptic dysfunction, cognitive dysfunction and the formation of plaques in AD. Here we provide a historical overview on the origin of plaques and a discussion on potential biological and therapeutic implications of intraneuronal Abeta accumulation for AD.     

The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease.

The authors examined the hypothesis that senile plaques of Alzheimer's disease (AD) are formed by abnormal leakage of amyloidogenic precursors from brain capillaries by quantitative analysis of the spatial relationship between capillaries and amyloid plaques. Vibratome sections (40 mu) of the hippocampus, including the entorhinal cortex, obtained at autopsy from AD subjects, were immunostained with a monoclonal antibody to beta-protein and counterstained with rabbit serum to either the glucose transporter protein, a cerebral endothelial marker, or collagen type IV, a basal lamina marker. The authors found that while 60% to 77% of amyloid plaques were associated with capillaries, only 8% to 13% were penetrated by a capillary, the remainder being adjacent. To test whether 1) the area occupied by amyloid plaques or 2) the border zone (10-mu rim) surrounding amyloid plaques has a statistically higher density of capillaries than 3) the remaining gray matter, similarly double-stained 6-mu sections from five AD subjects were photographed and the capillary densities in the three areas calculated. Capillary density was significantly lower in 1) than in 3) and higher in 2) than in 3), while the combined area of 1) and 2) showed the same capillary density as 3). Similar results were obtained by using either the glucose transporter or the collagen type IV antibodies. Because capillary density is low within, and high in regions that immediately surround amyloid plaques, our findings suggest that amyloid plaques exclude capillaries or lead to their degeneration, or both. The latter possibility was investigated by triple-staining tissue sections with antibodies to beta-protein, glucose transporter, and collagen type IV. The proportion of glucose transporter-negative capillaries was not significantly different in areas inside or outside of the plaques. Thus, the authors found no evidence of basal lamina remnants consistent with capillary degeneration preferential to amyloid plaques. Although a small number of capillaries showed amyloid deposition just beneath the basement membrane, the authors conclude that capillaries play only a limited direct role, if any, in amyloid plaque formation, and that the apparent association of amyloid plaques and capillaries is no more than a chance contact.     

Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). The cognitive change in AD has been correlated to the characteristic pathologic lesions in the brain, senile plaques (SP) and neurofibrillary tangles. Senile plaques are the most consistent correlative marker in AD. We present preliminary data indicating that abundant SP are found in the brains of nondemented patients dying with or as a result of critical coronary artery disease (cCAD) compared to nonheart disease (non-HD) subjects; 15 of 20 cCAD patients contained SP and only two of 16 non-HD patients contained SP.     

Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer's disease brain

Insulin degrading enzyme, encoded by IDE, plays a primary role in the degradation of amyloid beta-protein (A beta), the deposition of which in senile plaques is one of the defining hallmarks of Alzheimer's disease (AD). We recently identified haplotypes in a broad linkage disequilibrium (LD) block encompassing IDE that associate with several AD-related quantitative traits. Here, by examining 32 polymorphic markers extending across IDE and testing quantitative measures of plaque density and cognitive function in three independent Swedish AD samples, we have refined the probable position of pathogenic sequences to a 3' region of IDE, with local maximum effects in the proximity of marker rs1887922. To replicate these findings, a subset of variants were examined against measures of brain A beta load in an independent English AD sample, whereby maximum effects were again observed for rs1887922. For both Swedish and English autopsy materials, variation at rs1887922 explained approximately 10% of the total variance in the respective histopathology traits. However, across all clinical materials studied to date, this variant site does not appear to associate directly with disease, suggesting that IDE may affect AD severity rather than risk. Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients.     

Neuronal and microglial involvement in beta-amyloid protein deposition in Alzheimer's disease.

This study was undertaken to localize amyloid precursor protein (APP) and to determine how APP might be released and proteolyzed to yield the beta-amyloid protein deposits found in senile plaques in the brains of Alzheimer's disease patients. We found that antibodies to recombinantly expressed APP labeled many normal neurons and neurites. In addition, dystrophic neurites in different types of senile plaques and degenerating neurons in the temporal cortex and hippocampus of Alzheimer's disease patients were immunostained. We also detected small clusters of dystrophic APP immunoreactive neurites that were not associated with beta-amyloid protein deposits. Microglia was involved in different types of senile plaques and often were associated closely with APP immunoreactive neurites and neurons. The greatest concurrence of APP immunoreactivity and reactive microglia was seen in the subiculum and area CA1, regions with a high density of congophilic plaques and subject to intense Alzheimer's pathology. Our findings suggest that neuronally derived APP is the source for senile plaque beta-amyloid protein, while microglia may act as processing cells.     

Cytoskeletal protein pathology and the formation of beta-amyloid fibers in Alzheimer's disease

Discovery of the abnormally phosphorylated tau in paired helical filaments, its accumulation preceding the formation of the tangles and the in vitro microtubule assembly defect suggest that an abnormality in the protein phosphorylation/dephosphorylation system is involved in the pathogenesis of Alzheimer cytoskeletal pathology. The levels of mRNA for the beta-amyloid precursor protein (beta APP) in the brain suggest that only a small deficiency in the processing of the precursor would be sufficient to account for the accumulation of beta-amyloid in Alzheimer brain. Identification of reticuloendothelial system cells responsible for the production/processing of beta-amyloid will help to elucidate the pathogenesis of the brain amyloidosis. The disproportionate accumulation of paired helical filaments and amyloid within the same affected brain and from disease to disease raises the possibility of different etiologies for each of these lesions coexisting in Alzheimer's disease.