Numerous Amyloid Plaques Research Articles

Oligomer Formation by Amyloid-β42 in a Membrane-Mimicking Environment in Alzheimer's Disease.

The brains of Alzheimer's disease (AD) patients contain numerous amyloid plaques that are diagnostic of the disease. The plaques are primarily composed of the amyloidogenic peptides proteins Aβ40 and Aβ42, which are derived by the processing of the amyloid pre-cursor protein (APP) by two proteases called β-secretase and γ-secretase. Aβ42 differs from Aβ40 in having two additional hydrophobic amino acids, ILE and ALA, at the C-terminus. A small percentage of AD is autosomal dominant (ADAD) and linked either to the genes for the presenilins, which are part of γ-secretase, or APP. Because ADAD shares most pathogenic features with widespread late-onset AD, Aβ peptides have become the focus of AD research. Fibrils formed by the aggregation of these peptides are the major component of plaques and were initially targeted in AD therapy. However, the fact that the abundance of plaques does not correlate well with cognitive decline in AD patients has led investigators to examine smaller Aβ aggregates called oligomers. The low levels and heterogeneity of Aβ oligomers have made the determination of their structures difficult, but recent structure determinations of oligomers either formed or initiated in detergents have been achieved. We report here on the structures of these oligomers and suggest how they may be involved in AD.

Distinctive Features of Histochemical and Immunohistochemical Techniques for Amyloid Plaque Detection in the Human Cerebral Cortex

Amyloid plaques (also known as senile plaques) are insoluble extracellular aggregates of the P-amyloid peptide that accumulate in the human brain under normal aging and Alzheimer disease. The aim of this work was to study distinctive features of amyloid plaque detection in the cerebral cortex of the elderly with histochemical and immunohistochemical techniques. Material and methods . This study included samples of brain cortex of humans, males and females, aged 79-98, n = 23. Histochemical detection of amyloid was performed using the Congo red and the sodium sulphate-Alcian Blue methods. Anti-amyloid fibrils OC antibodies were used for immunohistochemical identification of amyloid plaques, anti-GFAP antibodies were used for astrocyte detection, a double immunofluorescent OC/GFAP reaction was performed for simultaneous detection of amyloid plaques and astrocytes. Results. The study results have demonstrated that classical histochemical methods are not effective for identification of amyloid plaques in the human brain allowing detecting only isolated amyloid accumulations. Immunohistochemical reaction with application of anti-amyloid fibrils OC antibodies allows identifying numerous amyloid plaques and studying plaque morphology. Immunohistochemical reaction with application of GFAP, being an astrocyte marker protein, is also suitable for the primary analysis of the human brain samples for the presence or absence of amyloid plaques. The double OC/GFAP immunofluorescence protocol developed by the authors makes it possible to identify both amyloid plaques and astrocytes with high specificity, to further study their spatial relationship and to create 3D reconstructions giving comprehensive information about the structural features and spatial relationship of astrocytes and amyloid plaques.

Inhibitory effects of Tabernaemontana divaricata root extract on oxidative stress and neuronal loss induced by amyloid β25–35 peptide in mice

In Alzheimer's disease, there are numerous amyloid plaques, neurofibrillary tangles, and neuronal loss in several brain areas. Oxidative stress is involved in the mechanisms of Aβ-peptide induced neurotoxicity by the generation of free radical oxidative stress that may lead to neurodegeneration. Tabernaemontana divaricata has various medical properties in Thai folklore medicine including prevent forgetfulness or improve memory. The present study aimed to investigate the effects of T. divaricata root extract (TDE) on Aβ25–35 peptides induced neuronal loss and oxidative stress in mice. Male ICR mice were administered with vehicle or TDE (250, 500, and 1000 mg/kg b.w., p.o.) for 28 consecutive days. Then, these mice were given a single intracerebroventricular (i.c.v.) injection of Aβ25–35 or phosphate buffer saline (PBS) (10 μg/mouse). The novel object recognition (NOR) test was used to determine memory disturbance. In addition, the neuronal cells in the cerebral cortex and hippocampus were measured by using crystal violet staining and lipid peroxidation was determined by measuring the formation of thiobarbituric acid reactive substances. An i.c.v. injection of Aβ25–35 peptides could significantly induce memory impairment, increase level of lipid peroxidation including the neuronal loss in CA3 of hippocampus. However, the mice pretreated with TDE could prevent the memory loss, neuronal loss and decrease lipid peroxidation. These results suggest the potential therapeutic value in dementia of TDE through its antioxidant property.

Encephalopathy with amyloid angiopathy and numerous amyloid plaques with low levels of CSF Aβ1–40/Aβ1–42

A middle-aged male suffering from encephalopathy with cerebral amyloid angiopathy (CAA) with amyloid beta (Aβ) presented with initial symptoms of transient consciousness disturbance and left visual field photophobia. Lesions with aberrantly high signal on T2-weighted magnetic resonance imaging (MRI) of the brain appeared in the right temporal lobe posterior to the occipital lobe and spread to other areas. Brain biopsy revealed Aβ deposits in vascular walls and numerous diffuse plaques in parenchymal areas. Based on MRI findings, Initial corticosteroid therapy with beta methasone effectively improved the neurological symptoms of consciousness disturbance and motor deficits. After corticosteroid therapy was stopped at 4 weeks, recurrence occurred. Additional corticosteroids did not improve clinical symptoms and the patient progressed to a bed-ridden state with a severe consciousness disturbance. Notably, CSF Aβ1–42 and CSF Aβ1–40 decreased while the recurrent encephalopathy worsened. After intense deterioration, the patient became stable. CSF Aβ1–42 increased but remained at a very low level. This case of CAA encephalopathy with apolipoprotein E ϵ4/ϵ4 homozygosity showed Aβ deposits in vascular walls and numerous diffuse plaques in parenchymal areas. The clinical course suggests that reduction of CSF Aβ1–42 and Aβ1–40 might be related to clinical deterioration in cases of encephalopathy.

P1‐061: Cerebral encephalopathy with cerebral amyloid angiopathy and numerous amyloid plaques presenting aberrant low levels of CSF Aβ 40/1–42

P1‐061: Cerebral encephalopathy with cerebral amyloid angiopathy and numerous amyloid plaques presenting aberrant low levels of CSF Aβ 40/1–42

A Second Case of Gerstmann-Sträussler-Scheinker Disease Linked to the G131V Mutation in the Prion Protein Gene in a Dutch Patient

A rare case of Gerstmann-Sträussler-Scheinker disease in a 36-year-old Dutch man is reported. The clinical phenotype was characterized by slowly progressive cognitive decline, later followed by ataxia and parkinsonism. Neuropathologic findings consisted of numerous amyloid plaques in the cerebellum, which showed positive staining for the abnormal prion protein (PrP(Sc)). In addition, there were tau accumulations around numerous amyloid deposits in the cerebral cortex, striatum, hippocampal formation, and midbrain. There was no spongiform degeneration. Western blot analysis showed the co-occurrence of 2 distinct abnormal prion protein species comprising an unglycosylated, protease-resistant fragment of approximately 8 kd, which was found to be truncated at both N- and C-terminal ends by epitope mapping, and a detergent-insoluble but protease-sensitive form of full-length PrP(Sc). Sequence analysis disclosed a mutation at codon 131 of the prion protein gene (PRNP), resulting in a valine-for-glycine substitution (G131V). The patient was heterozygous at the polymorphic codon 129 and carried the mutation on the methionine allele. To our knowledge, this is the second family worldwide in which this mutation has been identified. Gerstmann-Sträussler-Scheinker disease should be considered in patients with a clinical diagnosis of familial frontotemporal dementia.

Variant Creutzfeldt–Jakob disease: the first confirmed case from Portugal shows early onset, long duration and unusual pathology

We present clinical and autopsy findings in the first case of variant Creutzfeldt–Jakob disease diagnosed and confirmed in Portugal. Onset was at 11 years, the earliest onset reported, and the...

Alzheimer’s disease: a challenge for modern neuropathobiology

Springer-Verlag 2009 The clinical entity known as Alzheimer’s disease (AD) clearly existed before 1907, when Alois Alzheimer described the clinical course and changes in the brain of a 55-year-old woman dying after a 4-year history of progressive dementia [2, 4]. In his report of Auguste D, he demonstrated neurofibrillary tangles (NFT) using the newly developed Bielschowsky silver impregnation method, and observed cortical ‘‘miliary foci’’ of senile plaques (SP), described by Blocq and Marinesco [7] 15 years before. Examination of the histologic slides of Auguste D’s brain recovered 1992 in Munich revealed numerous NFTs and amyloid plaques in the upper parts of cerebral cortex, but no hippocampus was available. The genotype was determined ApoE e3/3 [14]. In the second case, Johann F, a male aged 56 years [3], numerous amyloid plaques but no NFTs were found in the neocortex, and DNA extraction revealed ApoE e3/3 without APP mutations [13]. Later studies suggested a familial form of the ‘‘plaque only type’’ of AD [19]. The case of Auguste D marks the beginning of research in Alzheimer’s disease (term introduced by Kraepelin in 1910 [20]), now recognized as the most common cause of dementia in the elderly—the disease/ epidemy of the twenty-first century, and the focus of intensive research during the past three centuries [17, 23]. Recently revised research and consensus criteria for the diagnosis of the major dementing disorders, in combination with modern (neuroimaging and cerebrospinal fluid) biomarkers improved the clinical diagnostic accuracy of AD from 65 to 92–96% [10]. Neuropathologic studies using immunohistochemistry, modern molecular biologic and genetic methods can achieve a diagnosis/classification, based on homogenous definitions, harmonized interlaboratory methods and standards for the assessment of nervous system lesions, in about 99%, without, however, being able to clarify the causes/etiology of most of these disorders, including AD. The current algorithms for the neuropathologic diagnosis of AD, based on (semi-) quantitative and topographic assessment of plaques and tangles, despite reasonable interrater agreements, only consider the classical

Hydrogen Peroxide Is Generated during the Very Early Stages of Aggregation of the Amyloid Peptides Implicated in Alzheimer Disease and Familial British Dementia

Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar deposits of the beta-amyloid peptide (Abeta) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early "soluble oligomers" are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of Abeta, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of Abeta and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(1-40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.

Neuropathologic variants of sporadic Creutzfeldt–Jakob disease and codon 129 of PrP gene

To determine the contribution of methionine/valine (Met/Val) polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob disease. Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a conformational change of PrP and a variety of PrP deposits in the brain, some of which aggregate into amyloid plaques. The authors semiquantitatively assessed neuropathologic lesions and performed PrP immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died in France between 1994 and 1998. Met/Met cases (mild lesions mostly involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits, no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and distinct neuropathology: severe lesions heavily involving the hippocampal formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits, rare amyloid plaques). The course of Val/Val patients younger than age 55 was particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the pathology, suggesting a distinct variety. Polymorphism at codon 129 modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype enhances the production of proteinase-resistant PrP, and the Met/Val genotype facilitates its aggregation into amyloid plaques.

Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice

Synaptic transmission and plasticity were studied in the CA1 field of hippocampal slices from young and aged transgenic mice over-expressing a mutant form of the human amyloid precursor protein (PDAPP mice). The transgenic mice at 4–5 months of age, prior to the formation of amyloid-β peptide deposits in these animals, differed from non-transgenic control mice in three respects: (1) paired-pulse facilitation (PPF) was enhanced; (2) responses to high frequency stimulation bursts were distorted; (3) long-term potentiation (LTP) decayed more rapidly. More striking was the profound reduction in the size of synaptic responses and frequent loss of field potentials that were found in the transgenic mice at 27–29 months, an age at which they exhibit numerous amyloid plaques, neuritic dystrophy, and gliosis. Control mice at these ages did not show such dramatic effects. PPF was reduced in aged transgenic mice, compared to aged controls; however, LTP was still in evidence, although direct comparisons of its induction conditions in aged transgenic and control mice were compromised by the profound differences in field potentials between the two groups. These results point to two conclusions: (1) altered synaptic communication appears in PDAPP mice in advance of amyloid plaque formation and probably involves changes in presynaptic calcium kinetics; (2) the disturbances in synaptic transmission that appear when abundant plaques and Alzheimer's-like neuropathology are present in the transgenic mice are not necessarily accompanied by a disproportionate loss of long-term synaptic plasticity.

Cloning of the Presenilin 2 cDNA and Its Distribution in Brain of the Primate,Microcebus murinus: Coexpression with βAPP and Tau Proteins

A 1340-bp cDNA fragment encoding the lemurian presenilin 2 protein (PS2) was isolated from aMicrocebus murinusbrain cDNA library by PCR using oligonucleotide primers based on the nucleotide sequence of the human gene. Analysis of five isolated clones showed that the sequence encoded a 448-amino-acid open reading frame, 95.5% identical to the human and 93.5% identical to the mouse presenilin 2 sequences. However, neither the localization of the 2 positions in PS2 nor that of the 43 positions in PS1 associated with early onset Alzheimer's disease were changed. Expression of the presenilin 2 was detected by RT–PCR and compared with that of presenilin 1 and βAPP in the brain and in peripheral tissues (liver, kidney, and spleen). Immunohistochemistry with a specific polyclonal antiserum raised against a synthetic peptide from the N-terminal part of the human PS2 showed that the protein is distributed throughout the microcebe brain, in vascular and nerve structures. In cortical and in subcortical areas, PS2 labeling was weak and granular in appearance and was scattered throughout the cytoplasm of many neurones, extending into neurites. The gene expression of PS2 increased with age but was not affected by the presence of numerous amyloid plaques. Double labeling immunocytochemistry detected very few neurones with combined immunoreactivity PS2 and APP, or PS2 and Tau.

Amyloid plaques in Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex contain species of A beta similar to those found in the amyloid plaques of Alzheimer's disease and pathological aging.

The Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is characterized by abundant neurofibrillary pathology and neuron loss. In contrast to Alzheimer's disease (AD), where extensive neurofibrillary lesions always occur with deposits of A beta in numerous amyloid plaques, A beta-rich amyloid plaques are absent or rare in most ALS/PDC patients. To characterize the amyloid plaques in the latter patients, we probed plaque-rich sections of their brains by immunohistochemistry using well-characterized antibodies to specific epitopes in the N and C termini of A beta as well as to defined epitopes in hyperphosphorylated tau (PHFtau). The results indicate that the species of A beta in the amyloid plaques of ALS/PDC patients resemble those detected in the amyloid plaques of cognitively intact subjects with pathological aging as well as patients with AD. However, the paucity of PHFtau-positive neurites in the ALS/PDC plaques suggests that they reflect pathological aging rather than AD.

Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis

In 1911, Alois Alzheimer published a detailed report (Zbl. ges. Neurol. Psych. 4: 356-385) on a peculiar case of the disease that had been named after him by Emil Kraepelin in 1910. Alzheimer describes a 56-year-old male patient (Johann F.) who suffered from presenile dementia and who was hospitalized in Kraepelin's clinic for more than 3 years. Post-mortem examination of the patient's brain revealed numerous amyloid plaques but no neurofibrillary tangles in the cerebral cortex, corresponding to a less common form of Alzheimer disease which may be referred to as 'plaque only'. We have identified well-preserved histological sections of this case and performed mutational screening of exon 17 of the amyloid precursor protein gene and genotyping for apolipoprotein E alleles. The patient was shown to be homozygous for apolipoprotein allele epsilon3 and lacked APP mutations at codons 692, 693, 713 and 717. This case is of historical importance as it may have convinced Kraepelin to name the disease after his co-worker, Alois Alzheimer.

Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.

Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.

A variant of Gerstmann-Sträussler-Scheinker disease carrying codon 105 mutation with codon 129 polymorphism of the prion protein gene: A clinicopathological study

A case was reported of variant Gerstmann-Sträussler-Scheinker disease (GSS) carrying codon 105 mutation (Pro to Leu) with codon 129 polymorphism (Met/Val) of the prion protein (PrP) gene. The male patient had developed clumsiness of the right hand at age 42, and subsequently exhibited slowly progressive spastic paraparesis, ataxia, dysarthria, memory disturbance and apraxia. Myoclonus or periodic synchronous discharge was not observed. He died at age 53. The cerebral cortex and white matter showed atrophy, which was prominent in the frontal regions. There were numerous amyloid plaques throughout the cerebral cortex, which were reactive with the antibody to PrP, but not to beta A4 peptide. PrP immunostaining also revealed many amorphous deposits in the deep cortical layers, where neuronal loss and glial proliferation was evident. The cerebellum was almost intact, except a few amyloid plaques in the white matter. This variant GSS with codon 105 mutation has been found in four pedigrees, only in Japan up to the present, and the clinicopathological phenotype is summarized as follows: (1) onset at age 38–48, with a duration of 7–11 years, (2) prominent spastic paraparesis, associated with dementia and ataxia, (3) numerous amyloid plaques in the cerebral cortex, (4) amorphous PrP deposits with neuronal loss in the deep cortical layers, and (5) minor change of cerebellum.

Lesions in the Pulvinar in Patients with Alzheimerʼs Disease

The pulvinar nucleus of the thalamus has been implicated in visual attention and in the control of eye movements, and may also help mediate attention-dependent tasks in the auditory and somatosensory systems. Consequently, a hypothetical disruption of functions mediated by the pulvinar may help understand common visual and nonvisual symptoms in patients with Alzheimer's disease. To test this hypothesis, the pulvinar nuclei of nine patients with histologically confirmed Alzheimer's disease and twelve young (9-28 years of age) and age-matched controls (without dementia and with non-Alzheimer dementias) were examined using a battery of histopathological methods. All patients with Alzheimer's disease had numerous amyloid plaques and some neuritic plaques throughout the various subdivisions of the pulvinar. Neuropil threads were also present among the senile plaques, and neurofibrillary tangles occurred in clusters throughout the nucleus. Control patients with and without dementia had very few Alzheimer lesions, which should be expected in normal elderly individuals. The lesions in the pulvinar may help understand some of the clinical manifestations of Alzheimer's disease, including deficits in attention and in a host of visual disturbances. Such deficits may be the result of involvement of reciprocal thalamo-cortical and corticothalamo-cortical circuits that appear to be critical for the function of a vast expanse of association cortices interconnected with the pulvinar, which are heavily laden with lesions themselves.

A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesis.

We report the clinicopathological findings of 5 patients with an inherited prion disease with a codon 105 (Pro to Leu) mutation. All of the patients had a spastic gait disturbance and progressive dementia without either cerebellar signs, myoclonus, or periodic synchronous discharges. Autopsy of 3 patients revealed numerous amyloid plaques in the cerebral cortex, especially in the motor cortex and the frontal lobe where neuronal loss and severe gliosis were observed in the absence of spongiform changes. The cerebellum was preserved histologically except for only a few amyloid plaques. The pyramidal tracts in the brainstem and spinal cord showed vacuolated changes and a loss of myelin, but no prion protein accumulations. Thus, the prion protein codon 105 mutation is considered to correspond to a new variant of the Gerstmann-Sträussler syndrome with spastic paraparesis.

Early‐onset Alzheimer's disease in 2 large Belgian families

Familial Alzheimer's disease (FAD) is a dominantly inherited condition that may present with an early onset, and myoclonus occurs frequently in the course of the disease. We report clinical and neuropathologic data on 2 large Belgian families with FAD in which we obtained 17 autopsies of the CNS. In family A, each of 11 autopsies had the typical neuropathologic features of Alzheimer's disease (AD), and there were a few cerebellar plaques in the molecular layer. In family B, in addition to the typical characteristics of AD in 6 autopsies, there were numerous amyloid plaques in the cortical cerebellar layers. In both families, we immunostained the amyloid deposits for the A4 protein, and they were negative for prion-associated protein immunoreactivity.

Familial dementia with PrP‐positive amyloid plaques

We present a 22-year follow-up of a large and unusual kindred previously reported as familial Alzheimer's disease (FAD). However, detailed clinical and neuropathologic evaluation of family members and brain autopsy on another affected individual now make the diagnosis of FAD unlikely. Our patient, as well as members of this family, had numerous amyloid plaques and rare neurofibrillary tangles. These plaques were quite atypical for Alzheimer's disease (AD); many were quite large (up to 500 microns in diameter) and contained several amyloid cores, some with neuritic components. The plaques were present throughout the cerebral cortex and striatum, but not in the cerebellum. By electron microscopy, they had radiating star-shaped amyloid cores containing 8- to 10-nm fibrils, and a few dystrophic neurites. They were strongly immunoreactive with antiserum to prion protein but did not react with the antiserum to the amyloid A4 protein of AD. Although the cerebellum was uninvolved, this family appears to represent another clinical and neuropathologic variant of Gerstmann-Sträussler syndrome.