Laminar distribution of β-amyloid deposits in dementia with Lewy bodies and in Alzheimer's disease

This study tested whether the laminar distribution of the β-amyloid (Aβ) deposits in dementia with Lewy bodies (DLB) cases with significant Alzheimer's disease (AD) pathology (DLB/AD) was similar to "pure" AD. In DLB/AD, the maximum density of the diffuse and primitive deposits occurred either in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. A bimodal distribution of the classic Aβ deposits was also observed. Compared with AD, DLB/AD cases had fewer primitive deposits relative to the diffuse and classic deposits; the primitive deposits exhibited a bimodal distribution more frequently, and the diffuse deposits occurred more often in the upper laminae. These results suggest that Aβ pathology in DLB/AD may not simply represent the presence of associated AD. © 2006 Sage Publications.

Classic beta-amyloid deposits cluster around large diameter blood vessels rather than capillaries in sporadic Alzheimer's disease

Various hypotheses could explain the relationship between beta-amyloid (Abeta) deposition and the vasculature in Alzheimer's disease (AD). Amyloid deposition may reduce capillary density, affect endothelial cells of blood vessels, result in diffusion from blood vessels, or interfere with the perivascular clearance mechanism. Hence, the spatial pattern of the classic ('cored') type of Abeta deposit was studied in the upper laminae (I,II/III) of the superior frontal gyrus in nine cases of sporadic AD (SAD). Sections were immunostained with antibodies against Abeta and with collagen IV to study the relationships between the spatial distribution of the classic deposits and the blood vessel profiles. Both the classic deposits and blood vessel profiles were distributed in clusters. In all cases, there was a positive spatial correlation between the clusters of the classic deposits and the larger diameter (>10 microm) blood vessel profiles and especially the vertically penetrating arterioles. In only 1 case, was there a significant spatial correlation between the clusters of the classic deposits and the smaller diameter (<10 microm) capillaries. There were no negative correlations between the density of Abeta deposits and the smaller diameter capillaries. In 9/11 cases, the clusters of the classic deposits were significantly larger than those of the clusters of the larger blood vessel profiles. In addition, the density of the classic deposits declined as a negative exponential function with distance from a vertically penetrating arteriole. These results suggest that the classic Abeta deposits cluster around the larger blood vessels in the upper laminae of the frontal cortex. This aggregation could result from diffusion of proteins from blood vessels or from overloading the system of perivascular clearance from the brain.

The spatial patterns of prion protein deposits in Creutzfeldt-Jakob disease:Comparison with β-amyloid deposits in Alzheimer's disease

Similar pathological processes may be involved in the deposition of extracellular proteins in the brains of patients with Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). Hence, this study compared the spatial patterns of prion protein (PrP) deposits in the cerebral cortex and hippocampus in cases of sporadic CJD with those of β-amyloid (Aβ) deposits in sporadic AD. PrP and Aβ deposits were aggregated into clusters and, in 90% of brain areas in CJD and 57% in AD, the clusters were regularly distributed parallel to the tissue boundary. In a significant proportion of cortical analyses, the mean diameter of the clusters of PrP and Aβ deposits were similar to those of the cells of origin of the cortico-cortical pathways. Aβ deposits in AD were distributed more frequently in larger-sized clusters than PrP deposits in CJD. In addition, in the hippocampus and dentate gyrus, clustering of Aβ deposits was observed in AD but PrP deposits were rare in these regions in CJD. The size, location and distribution of the extracellular protein deposits within the cortex of both disorders was consistent with the degeneration of the cortico-cortical pathways. Furthermore, spread of the pathology along these pathways may be a pathogenic feature common to CJD and AD. © 2001 Elsevier Science Ireland Ltd.

The spatial patterns of beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex in Alzheimer's disease

In Alzheimer's disease (AD) brain, beta-amyloid (Abeta) deposits and neurofibrillary tangles (NFT) are not randomly distributed but exhibit a spatial pattern, i.e., a departure from randomness towards regularity or clustering. Studies of the spatial pattern of a lesion may contribute to an understanding of its pathogenesis and therefore, of AD itself. This article describes the statistical methods most commonly used to detect the spatial patterns of brain lesions and the types of spatial patterns exhibited by ß-amyloid deposits and NFT in the cerebral cortex in AD. These studies suggest that within the cerebral cortex, Abeta deposits and NFT exhibit a similar spatial pattern, i.e., an aggregation of individual lesions into clusters which are regularly distributed parallel to the pia mater. The location, size and distribution of these clusters supports the hypothesis that AD is a 'disconnection syndrome' in which degeneration of specific cortical pathways results in the formation of clusters of NFT and Abeta deposits. In addition, a model to explain the development of the pathology within the cerebral cortex is proposed.

The spatial pattern of discrete beta-amyloid deposits in Alzheimer's disease reflects synaptic disconnection

The spatial pattern of discrete beta-amyloid (A beta) deposits was studied in the superficial laminae of cortical fields of different types and in the hippocampus in 6 cases of Alzheimer's disease (AD). In 41/42 tissues examined, discrete A beta deposits were aggregated into clusters and in 34/41 tissues (25/34 of the cortical tissues), there was evidence for a regular periodicity of the A beta deposit clusters parallel to the tissue boundary. The dimensions of the clusters varied from 400 to > 12,800 microns in different tissues. Although the A beta deposit clusters were larger than predicted, the regular periodicity suggests that they develop in relation to groups of cells associated with specific projections. This would be consistent with the hypothesis that the distribution of discrete A beta deposits in AD could reflect progressive synaptic disconnection along interconnected neuronal pathways. This implies that amyloid deposition could be a response to, rather than a cause of, synaptic disconnection in AD.

Dispersion of classic beta-amyloid deposits around blood vessels in Alzheimer’s disease

The spatial pattern of the classic (‘cored’) type of beta-amyloid (Abeta) deposit was studied in the upper laminae of the superior temporal gyrus in 9 cases of sporadic Alzheimer’s disease (SAD). Abeta stained tissue was counterstained with collagen IV to study the relationships between the spatial distribution of the classic deposits and the blood vessel profiles. Both the classic deposits and blood vessel profiles were distributed in clusters. In all cases, there was a spatial correlation between the clusters of the classic deposits and the larger diameter (>10 micron) blood vessel profiles and especially the vertically penetrating arterioles. In only 1 case, was there a significant spatial correlation between the clusters of the classic deposits and the smaller diameter (<10 micron) capillaries. In 9/11 cases, the clusters of the classic deposits were significantly larger than those of the clusters of the larger blood vessels. In addition, the density of the classic deposits declined as a negative exponential function with distance from the vertically penetrating arterioles. These results suggest that the classic Abeta deposits cluster around the larger blood vessels in the frontal cortex and that diffusion of proteins from these blood vessels could be involved in the pathogenesis of the classic deposits in SAD.

Factors determining the morphology of β-amyloid (Aβ) deposits in Down's syndrome

Immunostained preparations of the medial temporal lobe from patients with Down's syndrome (DS) were counterstained with cresyl violet to reveal the β-amyloid (Aβ) deposits and their associated cell populations. Aβ deposits in the cornu Ammonis (CA) of the hippocampus were, on average, more strongly stained, less often directly associated with neurons and more often associated with glial cells than the adjacent areas of cortex. Cored deposits were more frequently recorded in sulci rather than gyri and were associated with more glial cells than the uncored deposits. Multiple regression analyses suggested there was a positive correlation in the cortex between Aβ deposit size and the frequency of closely associated neurons, the correlation being most significant with larger (>25 μm) neurons. The morphology of Aβ deposit was also correlated with the location of deposits in the cortex, CA and dentate gyrus but this factor was of lesser importance. No significant variation in the morphology of the Aβ deposits was associated with the presence of blood vessels within or adjacent to the deposit. The data suggest that neuronal cell bodies are important in the initial formation of Aβ deposits and glial cells with the development of more mature amyloid deposits.

Amyloid diseases at old age : a pathological, epidemiological, and genetic study

Along with the increased life span of individuals, the burden of old age-associated diseases has inevitably increased. Alzheimer s disease (AD), probably the most well known geriatric disease, belongs to the old age-associated amyloid diseases. The purpose of this study was to investigate the frequency, genetic and health-associated risk factors, mutual association, and amyloid proteins in two old age-associated amyloid disorders senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) as part of the prospective population-based Vantaa 85+ autopsy study on a Finnish population aged 85 years or more (Studies I-III), completed with a case report on a patient with advanced AGel amyloidosis (Study IV). The numbers of patients investigated in the studies (I-III) were 256, 74, and 63, respectively. The diagnosis and grading of amyloid were based upon histological examination of tissue samples obtained post mortem and stained with Congo red. The amyloid fibril and associated proteins were characterized by immunohistochemical staining methods. The genotype frequencies of 20 polymorphisms in 9 genes and information on health-associated risk factors in subjects with and without SSA and CAA were compared. In a Finnish population ≥ 95 years of age, SSA and CAA occurred in 36% and 49% of the subjects, respectively. In total, two-thirds of these very elderly individuals had SSA, CAA, or both. However, in only 14% of the population these two conditions co-occurred. In subjects 85 years or older, the prevalence of SSA was 25%. In this population, SSA was associated with age at the time of death (p=0.002), myocardial infarctions (MIs; p=0.004), the G/G (Val/Val) genotype of the exon 24 polymorphism in the alpha2-macroglobulin (α2M) gene (p=0.042) and with the H2 haplotype of the tau gene (p=0.016). In contrast, the presence of CAA was strongly associated with APOE e4 (p=0.0003), with histopathological AD (p=0.0005), and with clinical dementia (p=0.01) in both e4+ (p=0.02) and e4- (p=0.06) individuals. Apart from demonstrating the amyloid fibril proteins, complement proteins 3d (C3d) and 9 (C9) were detected in the amyloid deposits of CAA and AGel amyloidosis, and α2M protein was found in fibrous scar tissue close to SSA. In conclusion, this first population based study on SSA shows that both SSA and CAA are common in very elderly individuals. Old age, MIs, the exon 24 polymorphism of the α2M gene, and H1/H2 polymorphism of the tau gene associate with SSA while clinical dementia and APOE ε4 genotype associate with CAA. The high prevalence of CAA, combined with its association with clinical dementia independent of APOE genotype, neuropathological AD, or SSA, also highlights its clinical significance in the very aged, among which the serious end stage complications of CAA, namely multiple infarctions and hemorrhages, are rare. The report on a patient having advanced AGel amyloidosis added knowledge on the disease and showed that this generally benign condition occasionally may lead to death. Further studies are warranted to confirm the findings in other populations. Also, the role of α2M and tau in the pathogenesis of SSA and the involvement of complement in the process of amyloid beta (Aβ) protein elimination from the brain remain to be clarified. Finally, the high prevalence of SSA in the elderly raises the need for prospective clinical studies to define its clinical significance.

Rapid label-free detection of metal-induced Alzheimer's amyloid beta peptide aggregation by electrochemical method

Amyloid beta peptide plays a critical role in the pathogenesis of Alzheimer's disease (AD). Metal ions are highly enriched in cerebral amyloid deposits in AD and are proposed to be able to mediate A beta conformation. Therefore, a rapid, low-cost, and sensitive detection of metal-induced A beta aggregation and their relation to AD is clearly needed for the clinical diagnosis and treatment. In this report, we study metal-induced A beta aggregation by a rapid, label-free electrochemical method and monitor both the aggregation kinetics and the morphology in the absence or presence of Zn (II) and Cu (II).

A cetylcholinesterase is increased in mouse neuronal and astrocyte cultures after treatment with b-amyloid peptides

The cellular origin of the acetylcholinesterase (AChE) associated with amyloid plaques in the Alzheimer’s disease (AD) brain is unknown. In this study we report that amyloid β-peptides (Aβ) increased AChE levels in both neuronal and astrocytic primary cultures, supporting the possibility that both neurons and glia may make a direct contribution to the pool of AChE seen around amyloid deposits in the AD brain.

Matrix Metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide

Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but nontransgenic islets do not, a broad spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.

Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Early Amyloid-like Oligomers and Their Implication in alpha-Synuclein Aggregation

Lewy bodies and Lewy neurites, neuropathological hallmarks of several neurological diseases, are mainly made of filamentous assemblies of alpha-synuclein. However, other macromolecules including Tau, ubiquitin, glyceraldehyde-3-phosphate dehydrogenase, and glycosaminoglycans are routinely found associated with these amyloid deposits. Glyceraldehyde-3-phosphate dehydrogenase is a glycolytic enzyme that can form fibrillar aggregates in the presence of acidic membranes, but its role in Parkinson disease is still unknown. In this work, the ability of heparin to trigger the amyloid aggregation of this protein at physiological conditions of pH and temperature is demonstrated by infrared and fluorescence spectroscopy, dynamic light scattering, small angle x-ray scattering, circular dichroism, and fluorescence microscopy. Aggregation proceeds through the formation of short rod-like oligomers, which elongates in one dimension. Heparan sulfate was also capable of inducing glyceraldehyde-3-phosphate dehydrogenase aggregation, but chondroitin sulfates A, B, and C together with dextran sulfate had a negligible effect. Aided with molecular docking simulations, a putative binding site on the protein is proposed providing a rational explanation for the structural specificity of heparin and heparan sulfate. Finally, it is demonstrated that in vitro the early oligomers present in the glyceraldehyde-3-phosphate dehydrogenase fibrillation pathway promote alpha-synuclein aggregation. Taking into account the toxicity of alpha-synuclein prefibrillar species, the heparin-induced glyceraldehyde-3-phosphate dehydrogenase early oligomers might come in useful as a novel therapeutic strategy in Parkinson disease and other synucleinopathies.

Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer's disease

We quantified the amount of amyloid β-peptide (Aβ) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APPV717F+/− TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APPV717F+/− Apoe−/− TG mice as old as 22 mo of age, whereas age-matched APPV717F +/− Apoe+/− and Apoe+/+ TG mice display abundant amyloid deposition. The amount of Aβ immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe+/+ > Apoe+/− ≫ Apoe−/−), and no Aβ immunoreactivity was detected in the cerebral cortex of APPV717F+/− Apoe−/− TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both Aβ1–40 and Aβ1–42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APPV717F TG mice. ApoE immunoreactivity was detected in a subset of Aβ immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APPV717F transgene nor its processing to Aβ peptide(s), we postulate that apoE promotes both the deposition and fibrillization of Aβ, ultimately affecting clearance of protease-resistant Aβ/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.

Characterization of serum amyloid A protein mRNA expression and secondary amyloidosis in the domestic duck

Secondary amyloidosis is a common disease of water fowl and is characterized by the deposition of extracellular fibrils of amyloid A (AA) protein in the liver and certain other organs. Neither the normal role of serum amyloid A (SAA), a major acute phase response protein, nor the causes of secondary amyloidosis are well understood. To investigate a possible genetic contribution to disease susceptibility, we cloned and sequenced SAA cDNA derived from livers of domestic ducks. This revealed that the three C-terminal amino acids of SAA are removed during conversion to insoluble AA fibrils. Analysis of SAA cDNA sequences from several animals identified a distinct genetic dimorphism that may be relevant to susceptibility to secondary amyloid disease. The duck genome contained a single copy of the SAA gene that was expressed in liver and lung tissue of ducklings, even in the absence of induction of acute phase response. Genetic analysis of heterozygotes indicated that only one SAA allele is expressed in livers of adult birds. Immunofluorescence staining of livers from adult ducks displaying early symptoms of amyloidosis revealed what appear to be amyloid deposits within hepatocytes that are expressing unusually high amounts of SAA protein. This observation suggests that intracellular deposition of AA may represent an early event during development of secondary amyloidosis in older birds.