Henryk M. Wisniewski's research while affiliated with New York State Institute for Basic Research in Developmental Disabilities and other places
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Publications (239)
The clinical course and expression of dementia in persons with Down's Syndrome (DS) are poorly understood. While longitudinal studies are rare they provide the most accurate data since standardized psychological tests yield performances which show pronounced ‘floor effects’, except with mildly to moderately retarded persons. A review of the main ps...
Meningeal and cerebral blood vessels were studied in Alzheimer's disease (AD), Down's syndrome (DS), and control brain specimens. Serial sections were double-and triple-immunostained for β-protein, smooth muscle cells, and leukocytes or macrophages/monocytes. At early stages of amyloidogenesis, β-protein immunoreactive material is present in vascul...
neuronal death;multiorgan organ;regional specialization;brain growth;integrated expression
Actomyosin complex was extracted from the brain cortex in a medium consisting of low salt, ATP, and EDTA, in the presence of protease inhibitors, followed by ammonium sulfate fractionation. Myosin was then purified from the actomyosin. Myosin obtained according to the procedure used was significantly contaminated with actin high (>200,000 dalton) a...
Clinical Diagnosis of Dementing DisorderClinical Diagnosis of Alzheimer's Disease (AD)SummaryAcknowledgementsReferences The Value of Inclusive Diagnostic Thinking and Appreciating Developmental Variance. Authored by Eric B. LarsonReflections on Retrogenesis. Authored by John O'BrienDementia: Diagnosis, Progression and Retrogression. Authored by Per...
Calbindin D(28K) (CB) expression was analyzed in the rat hippocampus following 10-min-cardiac arrest-induced ischemia within a year after reperfusion. In rats examined 3 days after ischemia, CB immunoreactivity disappeared completely from CA1 pyramidal neurons and from most CA2 pyramids. In the stratum granulosum of the dentate gyrus, mossy fibers,...
The term dementia has been useful in medical categorization and classification for approximately 2000 years. Although the term “dementia” has remained in usage over these past two millennia, in general, until the advent of the Renaissance, physicians who have followed the Galenic medical tradition, dating from the time of the Roman Emperor, Marcus...
Amyloid-beta (A beta) production, accumulation, and recycling were examined by light and electron microscopy in the pancreas of transgenic mice (from 45 days to 22 months of age) that express the gene for the carboxy-terminal fragment of the human amyloid-beta-protein precursor. Ultrastructural immunocytochemistry revealed four types of cells accum...
Previous epidemiological evidence suggested that in some instances a vector and/or reservoir is involved in the occurrence and spread of transmissible spongiform encephalopathies (TSEs). In a preliminary study, hay mite preparations from five Icelandic farms with a history of scrapie were injected into mice, and some of these mice became sick after...
The quantitative analysis of the claustrocortical connections in the rabbit, labeled with the fluorescent retrograde tracer Fluoro-Gold (FG), was conducted by means of unbiased stereology. The FG was injected into selected regions of the motor, somatosensory, auditory and visual cortices and then a comparison of the various claustrocortical project...
In brains with AD, Abeta is a major component of diffuse plaques. Previous reports showed that CSF Abeta42 levels were lower in patients with AD than in controls. Although studies showed higher plasma Abeta42 levels in familial AD, a recent report has indicated that plasma Abeta42 levels were similar in a sporadic AD group and controls. However, no...
The function of the neuronal high molecular weight microtubule-associated proteins (MAPs) MAP1b and MAP2 is regulated by the degree of their phosphorylation, which in turn is controlled by the activities of protein kinases and protein phosphatases (PP). To investigate the role of PP in the regulation of the phosphorylation of MAP1b and MAP2, we use...
A number of aspects of the pathogenesis of scrapie remain to be elucidated. The cellular and molecular aspects of the neuropathology in scrapie suggest the possibility that the proinflammatory cytokines could act as pathogenic mediators in this neurodegenerative disease. To understand this possibility, we examined the expression of proinflammatory...
The pattern of neuronal loss in the rat hippocampus following 10-min-long cardiac arrest-induced global ischemia was analyzed using the unbiased, dissector morphometric technique and hierarchical sampling. On the third day after ischemia, the pyramidal layer of sector CA1 demonstrated significant (27%) neuronal loss (P<0.05). At this time, no neuro...
An important gap in our understanding of the pathogenesis of the amyloidoses is the identification of the cellular events that lead from synthesis of an amyloid precursor protein to its conversion to the amyloid fiber subunit. We address this question by characterizing the effects of an amyloidogenic mutation on the intracellular processing of its...
Soluble amyloid beta-protein (Abeta) is normally present in the cerebrospinal fluid (CSF) and plasma. However, it is fibrillized and deposited as plaques in the brains of patients with Alzheimer's disease. Cerebrospinal fluid (CSF) contains several circulating proteins (apolipoprotein E, apolipoprotein J, and transthyretin) that bind to Abeta. We r...
Two (P117L; M146L) familial Alzheimer's disease (FAD)-causing presenilin-1 (PS1) mutations have been tested fortheir effect in stably transfected mouse neuroblastoma (N2a) cell lines. The P117L mutation is associated with the earliest onset of AD reported so far (24 years), while the M146L is less pathogenic with the onset at about 43 years. Overex...
The choroid plexus (CP) performs the vital function of producing up to 90% (450-1000 ml/day) of cerebrospinal fluid (CSF) to nourish and to protect the brain in the CSF suspension. The CP also acts as a selective barrier between blood and CSF to regulate ions and other essential molecules. However, the accumulation of intracellular inclusions calle...
Using a nonair-drying modification of a method for longitudinal sectioning of metaphase spreads on glass slides [Wen et al., 1997], we have studied 14 preidentified X chromosomes (10 from fragile X specimens and 4 controls) with transmission electron microscopy (TEM). Four of 10 X chromosomes from fragile X specimens exhibited lighter chromatin den...
Canine smooth muscle cells (SMCs), cultured from amyloid affected brain blood vessels accumulate Alzheimer amyloid-beta peptide (A beta) intracellularly. either spontaneously or after treatment with apolipoprotein E (apoE). ApoE is codeposited with A beta, which suggests that apoE participates in A beta accumulation. We tested the hypothesis that a...
In Alzheimer’s disease (AD), neurofibrillary degeneration of neurons starts in the transentorhinal cortex and spreads in
a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus – a key structure of the
memory system. People with Down’s syndrome (DS) develop neurofibrillary changes more than 30 years earlier...
Morphometry of the cerebellum of 11 subjects who died in the severe, final stage of Alzheimer's disease (AD) and of five age-matched subjects without dementia revealed significant atrophy in the AD group, with a decrease in the volume of the molecular layer by 24% and of the granular layer by 22% in comparison with controls. The 32% decrease in the...
Two-laser and two-color approaches were used to observe the colocalization of the calcium-binding proteins, calbindin D28k and parvalbumin, and the retrograde tracer, Fluoro-Gold (FG) in the basolateral amygdala of the rat. The study was performed on five adult rats into which FG was injected to the frontal association cortex. Then, the localizatio...
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is diagnosed definitively by increased numbers of beta-amyloid plaques and neurofibrillary tangles in brain biopsy or autopsy specimens. There are no simple straightforward laboratory tests currently available for clinical diagnosis. We have found consistent reduction in mitotic in...
ALZHEIMER'S disease (AD), a progressive neurodegenerative disorder, is diagnosed definitively by increased numbers of β-amyloid plaques and neurofibrillary tangles in brain biopsy or autopsy specimens. There are no simple straightforward laboratory tests currently available for clinical diagnosis. We have found consistent reduction in mitotic index...
In a series of multiple regression models predicting either duration or severity of Alzheimer disease (AD) patients, significant linear correlations were found consistently for the volume of CA1, the subiculum, and the entorhinal cortex. Similarly, the total number of neurons in CA1, CA4, and the subiculum was correlated significantly with both the...
A study of brains of 16 dogs from one to 19 years of age showed a structure- and cell-type- specific pattern of tau protein phosphorylation at mAb Tau-1 site and the absence of phosphorylation at the mAb AT8 site. Strong immunolabeling with mAb Tau-1 of the mossy fibers and perikarya of neurons in sectors CA3 and CA4 of the cornu Ammonis, less inte...
The presenilin-1 (PS1) gene mutation (Pro117Leu), recently identified in a Polish family is characterized by the earliest reported onset (from 24-31 years) of Alzheimer disease (AD) and a very short duration of disease (4-6 years). The neuropathology of 2 subjects with this PS1 mutation (ages at death: 35 and 37 years) was compared to four Down syn...
The numerical density of microglial cells is reduced by 47% in the corpus callosum, by 37% in the parietal cortex and by 34% in the frontal cortex of mice mutant at the op locus which are totally devoid of colony stimulating factor-1 (CSF-1), the major growth factor for macrophages. Moreover, microglia in the frontal cortex of the op/op mice are sm...
The total number of neurons with and without neurofibrillary changes in sectors CA1 to CA4, subiculum, and dentate gyrus of 16 subjects with Alzheimer disease (AD) was estimated. The duration of neurofibrillary changes was calculated on the basis of regressions between the duration of AD and neuronal numbers. In the CA1 and subiculum, it takes 3.4...
A characteristic feature of the parvopyramidal layer of the presubiculum of 6 individuals with Alzheimer disease (AD) was the presence of large, evenly distributed amyloid-beta (A beta) deposits, which in the end stage of the disease occupy 80.9 +/- 12.2 % of the parvopyramidal layer. The strong reaction of AP deposits with antibodies 4G8 (17-24 am...
Levels of soluble amyloid beta protein (sAbeta), amyloid beta precursor protein (APP) and apolipoprotein E (apoE) were examined in cerebrospinal fluid (CSF) obtained twice, at baseline and after 3-year follow-up, from 25 patients with probable Alzheimer's disease (AD). Levels of sAbeta and apoE from patients with the apoE4 allele decreased with tim...
Scrapie is a degenerative disease of the central nervous system of sheep and goats. The causative agent has been passaged to a number of laboratory species, including mice and hamster. Amyloid plaque formation and vacuolation, the signs of senile dementia, are found in the brains of mice infected with 87V scrapie agent. Dopamine (DA) and norepineph...
We compared the effect of serum from (a) 26 Alzheimer's disease (AD) patients and 22 age-matched non-demented controls (CO) with apolipoprotein E 4/4, 3/3 or 3/2 phenotypes, and (b) 17 normal young (aged 15-41 years) and 21 normal elderly (aged 64-83 years) people on in vitro aggregation of synthetic amyloid beta-protein (A beta) 1-40 by Thioflavin...
The life expectancy of people with mental retardation has dramatically increased over the past several decades. However, relatively little attention has been paid to the phenomenon of aging in this population, largely due to the historic fact that few of these people survived to become senior citizens. A rapidly expanding population of older adults...
Aging during the senior years is part of the normal process of life span development. We are born, mature, and if we are fortunate, we grow old before we die. Unfortunately, the process of growing old is associated with declining status in many respects, physical and cognitive. These declines can be related to the concept of reserve: the greater th...
This study investigated the time of expression of two endothelial cell adhesion molecules, ICAM-1/CD54 and PECAM-1/CD31 in the developing postpartum mouse blood-brain barrier (BBB). Immunoultrastructural studies demonstrated that both adhesion molecules are initially expressed primarily on the luminal endothelial cell surfaces at birth or shortly t...
Previously, by using in vivo microdialysis, we demonstrated a huge release of 45 Ca 2 from prelabeled tissues to dialysate that was evoked by application of N-methyl-D-aspartate (NMDA) to the rat dentate gyrus (DG) and sector 4 of the cornu ammonis. To establish the mechanism of this phenomenon, in the present study, we characterized its NMDA recep...
Amyloid beta protein 1-40 (A beta40) and A beta42 levels were quantitated in plasma from 43 persons with Down syndrome (DS; 26-68 years of age), 43 age-matched normal controls, and 19 non-DS mentally retarded (MR) persons (26-91 years of age) by using a sandwich enzyme linked immunosorbent assay. A beta40 levels were higher in DS and MR than contro...
Previously, by using in vivo microdialysis, we demonstrated a huge release of 45 Ca 2 from prelabeled tissues to dialysate that was evoked by application of N-methyl-D-aspartate (NMDA) to the rat dentate gyrus (DG) and sector 4 of the cornu ammonis. To establish the mechanism of this phenomenon, in the present study, we characterized its NMDA recep...
Previously, by using in vivo microdialysis, we demonstrated a huge release of 45 Ca 2 from prelabeled tissues to dialysate that was evoked by application of N-methyl-D-aspartate (NMDA) to the rat dentate gyrus (DG) and sector 4 of the cornu ammonis. To establish the mechanism of this phenomenon, in the present study, we characterized its NMDA recep...
Previously, by using in vivo microdialysis, we demonstrated a huge release of 45 Ca 2 from prelabeled tissues to dialysate that was evoked by application of N-methyl-D-aspartate (NMDA) to the rat dentate gyrus (DG) and sector 4 of the cornu ammonis. To establish the mechanism of this phenomenon, in the present study, we characterized its NMDA recep...
Previously, by using in vivo microdialysis, we demonstrated a huge release of 45 Ca 2 from prelabeled tissues to dialysate that was evoked by application of N-methyl-D-aspartate (NMDA) to the rat dentate gyrus (DG) and sector 4 of the cornu ammonis. To establish the mechanism of this phenomenon, in the present study, we characterized its NMDA recep...
There is compelling evidence for the early involvement of the hippocampal formation in the natural history of Alzheimer's disease (AD). The evidence comes from recent neuropathology, neuropsychology, and neuroimaging studies. AD-type histopathologic changes limited to the hippocampus have been described and may be seen in normal aging subjects. The...
To define the cellular processing of human cystatin C as well as to lay the groundwork for investigating its contribution to lcelandic Hereditary Cerebral Hemorrhage with Amyloidosis (HCHWA-I), we have characterized the trafficking, secretion, and extracellular fate of human cystatin C in transfected Chinese hamster ovary (CHO) cells. It is constit...
Evidence is accumulating that suggests that increased permeability of the BBB to blood-borne proteins is favorable for the development of neuropathologic changes such as amyloid angiopathy and formation of amyloid plaques in the AD brain. To study this problem, we applied a quantitative immunocytochemical procedure that enables evaluation of the ba...
Smooth muscle cells cultured from amyloid-beta-affected arteries accumulate amyloid-beta peptide A beta. We now show that accumulation of "A beta" deposits in this model can be significantly reduced by culture in conditioned media from microglia and monocytes. Reduced A beta accumulation was associated with (i) lower secretion of A beta, (ii) incre...
Smooth muscle cells (SMCs) isolated from amyloid-angiopathy affected brain vessels accumulate intracellularly amyloid-beta peptide (A beta). Now we demonstrate that accumulation of A beta in SMCs can be reduced by factors secreted by macrophages - IL-1alpha, IL-6, TNF-alpha, TGF-beta1 or PGE2 - probably by stimulating the non-amyloidogenic processi...
Amyloid beta-protein (A beta) is the major constituent of amyloid fibrils composing beta-amyloid plaques and cerebrovascular amyloid in Alzheimer's disease (AD). We studied the effect of metal cations on preformed fibrils of synthetic A beta by Thioflavin T (ThT) fluorescence spectroscopy and electronmicroscopy (EM) in negative staining. The amount...
Monoclonal antibodies (mAbs) D3G6 and C8A5, specific for amino acid residues 160-168 of S182 protein, immunolabeled neurons, ependymal and choroid plexus cells, and myocytes in brain sections from normal subjects and people with Alzheimer disease or Down syndrome and in rats and mice. Oligodendroglia, microglia, and the majority of astrocytes were...
The total numbers of neurons with and without neurofibrillary changes in the hippocampal subdivisions were estimated in 16 subjects with Alzheimer disease (AD) and in 5 normal elderly controls. On the basis of clinical symptoms, AD patients were subdivided into relatively less (AD-1. Functional Assessment Staging [FAST] stages 7a to 7c) and more se...
Vitamin E (α-tocopherol) was isolated from garlic. The method involved homogenization of garlic in phosphate-buffered saline and extraction with heptane in the presence of lithium dodecyl sulfate. An aliquot of the extract, when analyzed by HPLC on a C18 column, yielded a peak with the same retention time as the α-tocopherol standard. The presence...
In vitro aggregation and fibrillization of synthetic amyloid beta-protein Abeta 1-40 was assessed in the conditioned media from rhabdomyosarcoma (CRL 1598, HTB 82, HTB 153, CCL 136), adenocarcinoma (CCL 218), neuroblastoma (SY5Y), and COS cells cultured in the absence and presence of 10% heat-inactivated fetal bovine serum (FBS). The aggregation an...
In a search for Alzheimer β-amyloid peptide precursor ligands, Potempska et al. (Arch. Biochem. Biophys. (1993) 304, 448) found that histones bind with high affinity and specificity to the secreted precursor. Because exogenous histones can be cytotoxic, we compared the effects of histones on the viability of cells which produce little β-amyloid pep...
Smooth muscle cells cultured from leptomeningeal vessels from old dogs with amyloid-angiopathy accumulate intracellular deposits that are immunoreactive for amyloid-[beta] peptide (A[beta]). We used this cellular model in the present study to examine the influence of sera and cerebrospinal fluid on intracellular accumulation of A[beta]-immunoreacti...
We developed a method for the preparation of ultrathin longitudinal sections of chromosomes enabling TEM studies of whole chromosomes. By using a novel "repeat chill" method of exposing the glass slide and plastic block interface to liquid nitrogen, it was possible to separate consistently hardened epoxy resin-embedded chromosome spreads from glass...
Down's syndrome (DS) patients show accelerated Alzheimer's disease (AD) neuropathology, which consists of preamyloid lesions followed by the development of neuritic plaques and neurofibrillary tangles. The major constituents of preamyloid and neuritic plaques are amyloid beta (Abeta) peptides. Preamyloid lesions are defined as being Abeta immunorea...
Aggregation of Alzheimer’s amyloid-β peptide (Aβ) and formation of amyloid plaques and vascular amyloid are considered a cause of dementia of the Alzheimer’s type. The mechanisms and/or agents that trigger fibrillization of Aβ, which could be the targets of rational therapy for Alzheimer’s disease (AD), are still unknown. The lack of appropriate ex...
The three-dimensionally reconstructed hippocampal formations in three patients with very severe, immobile Alzheimer disease (AD) and three age-matched nondemented individuals were examined for a correlation between atrophy of hippocampal formation subdivisions and neurofibrillary changes, neuronal loss, and extent of amyloid deposition in plaques a...
We examined the effect of cerebrospinal fluid (CSF) from 23 Alzheimer's disease (AD) patients and 22 age-matched non-demented controls with apolipoprotein E4/4, 3/3, or 3/2 phenotypes on in vitro aggregation of amyloid beta-protein (A beta) 1-40 by Thioflavin T fluorescence spectroscopy. CSF from both AD and control groups inhibited A beta aggregat...
A study of the brains of 30 dogs, mongrels from 6.5 to 26.5 years of age, revealed that all dogs older than 13 years of age develop amyloid-beta-positive plaques. Cluster analysis based on the age of the dogs and the numerical density of amyloid-positive plaques stained with monoclonal antibody 4G8 (17-24aa) revealed that the population of old dogs...
Dulbecco's modified Eagle's medium promotes aggregation and fibrillization of the synthetic amyloid beta 1-40 and beta 1-42 peptides more than RPMI and OPTI media. Fibrillization in all of these media is faster than in phosphate-buffered saline and Tris buffer. Normal and heat-inactivated fetal bovine and human serum abolish amyloid fibril formatio...
Most early-onset familial Alzheimer disease is associated with missense mutations in S182, a membrane protein on chromosome 14. We investigated amyloid-beta protein (A beta) precursor (A beta PP) metabolism in skin fibroblasts from S182 (Glu246)-affected individuals and unaffected family members. Steady-state A beta PP levels were similar among all...
Our morphometric study of 30 dogs, mongrels, from 6.5 to 26.5 years of age, shows amyloid angiopathy in cortical and leptomeningeal vessels of all dogs older than 13.2 years of age, and the increase in the numerical density of amyloid-positive vessels correlated with age. Cluster analysis distinguished the group of six dogs (25%) to be relatively l...
In this article, we present a clinical description of Alzheimer's disease, review extant literature regarding the prevalence of dementia of the Alzheimer's type in people with Down syndrome, and discuss the relationship between Alzheimer's-type neuropathology and Alzheimer's type dementia in people with Down syndrome. After reaching the age of 30 y...
Most early-onset familial Alzheimer disease is associated with missense mutations in S182, a membrane protein on chromosome 14. We investigated amyloid-[beta] protein (A[beta]) precursor (A[beta]PP) metabolism in skin fibroblasts from S182 (Glu246)-affected individuals and unaffected family members. Steady-state A[beta]PP levels were similar among...
Cultured brain vascular smooth muscle cells (SMCs) accumulate beta-peptide in intracytoplasmic granules [9,10,33]. We show here that apoE3 and E4 induces the intracytoplasmic beta-peptide accumulation in cultured human and canine SMCs. The induction is dose-dependent and the accumulated granules also contain apoE and some were thioflavine S-positiv...
The distribution of intercellular adhesion molecule (ICAM-1) binding sites was studied in the microvasculature of several types of human brain tumor biopsies (angioma, glioblastoma multiforme and meningioma). Immunoelectron microscopy was performed with the application of immuno-HRP or -gold probes using a pre-embedding technique. Ultrastructural a...
The apoE phenotype of 83 patients with probable Alzheimer's disease (AD) and of 164 non-demented controls was determined by isoelectric focusing and Western blotting. The proportion of the e4 allele was 0.548 in AD and 0.202 in controls (P4 homozygotes was 18-fold greater than in individuals without the 4 allele. ApoE concentrations were measured i...
That the topography, severity, and progression of beta-amyloid deposition in the brain of Alzheimer's disease (AD) and Down's syndrome (DS) cases is not uniform is well documented. We have addressed at present, the issue of whether the structural composition of beta-peptide (A beta) within the early amyloid deposits might contribute to this phenome...
Cultured smooth muscle cells isolated from beta-amyloid-affected blood vessels from old dogs accumulate beta-protein at early passages [5,24]. Now, we show that smooth muscle cells derived from amyloid-free brain blood vessels and peripheral arteries from old and young animals are induced by culture conditions to deposit intracellularly fibrillar a...
Thiamine deficiency (TD) is a classical model of impaired cerebral oxidation. As in Alzheimer's disease (AD), TD is characterized by selective neuronal loss, decreased activities of thiamine pyrophosphate-dependent enzymes, cholinergic deficits and memory loss. Amyloid β-protein (Aβ), a ∼4 kDa fragment of the β-amyloid precursor protein (APP), accu...
Our recent results indicate that in Alzheimer's disease (AD) amyloid angiopathy, smooth muscle cells are responsible for beta-amyloid deposition in the vascular wall. Aged dogs have been shown to develop beta-amyloid angiopathy similar to that in AD. Thus, we used brain and peripheral vessels from aged and young dogs to isolate cells of the vascula...
Loss of nerve cells is a hallmark of the pathology of Alzheimer's disease (AD), yet the patterns of cell death are unknown. By analyzing DNA fragmentation in situ we found evidence for cell death not only of nerve cells but also of oligodendrocytes and microglia in AD brains. In average, 30 times more brain cells showed DNA fragmentation in AD as c...
Polyclonal antiserum against a high molecular weight glycosylated protease, purified from calf brain cytosol, was raised in rabbit and purified by immunoaffinity. The antibody specifically immunoreacted with the M(r) = 165,000 and 155,000 polypeptides of the protease. Immunocytochemical localization data revealed that the protease is localized in t...
Loss of nerve cells is a hallmark of the pathology of Alzheimer's disease (AD), yet the patterns of cell death are unknown. By analyzing DNA fragmentation in situ we found evidence for cell death not only of nerve cells but also of oligodendrocytes and microglia in AD brains. In average, 30 times more brain cells showed DNA fragmentation in AD as c...
Meningeal blood vessels were studied in Alzheimer disease (AD) and control brain specimens obtained from autopsies within 16 hours after death. Serial sections were stained with thioflavine S and Congo red and immunostained for the presence of beta-amyloid precursor protein (beta PP) and beta-protein and for smooth muscle-specific proteins myosin,...
In dogs under 17 years of age no amyloid deposits were observed in the claustrum. After that age amyloid deposits were found in all the brains studied. The number of amyloid deposits increases rapidly between 17 and 19 years of age. In none of the animals were neurofibrillary tangles found. However, in almost all claustra with amyloid deposits the...
Aluminum, the third most common element in the earth's crust (second to oxygen and silicon) and recently suspected by some investigators to be implicated in Alzheimer disease etiology, has been studied in relation to its effect on mitogenesis, mitosis, and cell cycle. We have observed that 2–4 mM concentrations of AlCl 3 have decreased the number o...
The clinical histories of 102 schizophrenics who died at 70 years of age or older were reviewed. The incidence of neurofibrillary tangles (NFTs) was two times higher in the patients who received (74%) than in those who did not receive (36%) treatment with neuroleptics. The development of NFTs started earlier in the treated group. Further studies co...
Neuropathological implications for Alzheimer disease (AD) treatment are based on several basic observations. There appears to be more than one cause of development of AD neuropathology and therefore, AD might be considered a syndrome. The duration of both the clinical and the preclinical course is very long. Discoveries of the proteins (ß-peptide,...
Amyloid beta-protein (A beta) is the major protein of cerebrovascular and plaque amyloid in Alzheimer's disease (AD). Extensive evidence has demonstrated abnormal protein phosphorylation in this disease. We investigated the effect of synthetic A beta with the amino-acid sequence corresponding to cerebrovascular A beta and plaque A beta on the activ...
The claustrum is a large subcortical structure that in animals possesses extensive connections with almost all regions of the cerebral cortex. Because there are no data that support the presence of claustrocortical connections in human brain, the main aims of the present study were to confirm the existence of these connections in the human brain. F...
Alzheimer neurofibrillary tangles (NFT) and senile plaque core amyloid (SPCA) isolated from the brain of patients with Alzheimer's disease were freeze-dried and replicated with a new platinum-carbon (Pt-C) vertical deposition method for high-resolution transmission electron microscopy (TEM). The resolution of this vertical Pt-C replication method i...
To explore the utility of cultured skin fibroblasts in investigating diseases of the nervous system in which constituents characteristic of neurons are involved, sensitive immunochemical methods were used to test for the presence in skin fibroblasts of low amounts of proteins normally used as neuronal markers. The presence of each of the neurofilam...
Point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 (ND2) were detected in 10 of 19 Alzheimer's brains but not in 11 normal brains. The same mutations were also detected in 2 of 6 patients with amyotrophic lateral sclerosis (ALS). However, neurofibrillary tangles and neuritic plaques characteristic of Alzheimer's disease were...
In two of six brain biopsies of patients with Alzheimer's disease (AD), tubuloreticular structures (TRS) were observed in the distended endoplasmic reticulum of microglial cells, endothelial cells of vessels, and pericytes. In the microglial cells that produce amyloid fibrils, TRS were found in the cytoplasmic channels, which were filled with newly...
Alzheimer’s disease (AD) is the most common illness characterized by the accumulation of amyloid. It was first described by Alois Alzheimer in 1907, when it was regarded as a rare and inconsequential neuropathological entity. However, since that time there has been a major reappraisal of the pathological basis of common senile dementia. AD is now k...
It was Oscar Wilde who defined the tragedy of old age by saying that " . . . as soon as you are old enough to know better, you don't know anything at all. " As improvements in the quality of health care bring about longer life, our attention has turned from the prolonging of life to the maintenance of involvement in life. In developed nations, a fu...
Neurofibrillary changes are characteristic of the brains of individuals with Alzheimer's disease (AD) and of those with Down syndrome. Neurofibrillary tangles (NFT) are also seen in small numbers in the brains of normal old people. They also occur in subacute sclerosing panencephalitis (SSPE), a fatal inflammatory disease induced by measles virus....
Citations
... These hair-like processes are about 0.1 m in diameter and 0.5-3 m long [10]. The density of the microvilli on the endothelial cell surface increases during ischemia and in hypertensive animals [11][12][13][14]. On the other hand, application of NO reduces the count and length of the endothelial microvilli [15]. ...
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... A study that examined primary rat cerebellar granule cells (CGC) treated with various combinations of N-methyl-D-aspartate (NMDA) receptor agonists, NMDA receptor antagonists, and nanosilver, found that nanosilver treatment increased intracellular calcium levels through NMDA receptor activation [113]. This is of note since this influx of calcium into the neuron stimulates calcium induced calcium release (CICR), as well as inositol 1,4,5-triphosphate receptors (IP3R)-mediated calcium release from the endoplasmic reticulum (ER) calcium reserves into the cytoplasm, leading to increased mitochondrial calcium levels and potentially to mitochondrial dysfunction [113,114]. Nanosilver treatment of human Chang liver cells at the EC 50 increased the mitochondrial calcium level in the cells by over two-fold, as was seen by flow cytometry with the Rhod2-AM fluorescent probe [115]. Rhod2-AM sequesters preferentially into the mitochondria due to its positive charge, as well as only fluorescing once it is oxidized which generally occurs in the mitochondria [115], thus making it useful in detecting mitochondrial calcium levels. ...
... Several studies have demonstrated that amiloride has neuroprotective properties using a dose of 10 mg/kg [27,[52][53][54]. Following this logic, we hypothesized that GCI-induced hippocampal damage can be protected by reducing intracellular zinc accumulation through inhibition of NHE-1 [27,55]. ...
... Mean brain weight in the AD subject group was insignificantly less (1085 g), and the decline did not correlate significantly with age (r ¼ 0.05); however, the correlation with the duration of AD was significant (r ¼ À0.63; p < 0.001). The study was performed by using coded brain tis- NFT Tau1 Amyloid 4G8 1 C 459-96 F -69 Pulmonary edema 48 1320 --II A 2 C 129-98 M -72 Myocardial infarct 3 1200 --IV C 3 C 456-96 M -73 Heart failure 48 1200 --III A 4 C 199-96 M -77 Abdominal hemorrhage 19 1270 --II A 5 C 402-00 F -78 Lymphoma 4 980 --III A 6 C 115-00 M -80 Lymphoma 7 1120 --III C 7 C 113-00 M -82 Bronchopneumonia 7 1140 --IV C 8 C (20), and other staging methods utilized in AD assessment reveal a floor effect with missing standards for assessment of functional deterioration during severe AD, whereas FAST stage 7 identifies the chronological order of functional loss in 6 substages (a-f) in the last 7 years of AD (21). Application of FAST estimates for the duration of 6 clinical substages of AD was a critical factor in attempting to detect dynamics of degeneration, neuronal loss, and functional deterioration in severe AD. ...
... This line of reasoning was strongly supported by the extensive work Henry performed on Down's syndrome patients, where he found that amyloid deposit preceded NFT pathology by many years [37,43,57,102,103,[124][125][126]. On the basis of this data, he concluded that amyloid deposits in AD start the process of neuropil pathology and not the other way around, as suggested by many neuropathologists and neuroscientists [76,86,104,111,128]. This provided essential groundwork for the amyloid cascade hypothesis. ...
Reference: Henry M. Wisniewski M.D. Ph.D
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... From a neuropathological viewpoint, it is characterized by i) the presence of senile plaques, extracellular deposits primarily composed of a 39±43 amino acid peptide, termed b-amyloid peptide, Ab (3,4); ii) the presence of neuro®brillary tangles (NFTs), composed of phosphorylated tau protein, and iii) a neuronal loss, and particularly a synaptic loss, with brain atrophy (5±7). These pathological changes likely occur over a one or two decade duration prior to the loss of intellectual capacity (8). ...
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... In sporadic AD, the duration of the disease from FAST stage 3 to the onset of FAST stage 7f (loss of ability to hold head up or to move the head) is estimated to be 19 years on average (40,41). The presence of early pathological findings of AD during the approximately 15year-long FAST stage 2 indicates that the total duration of the disease is about 34 years. ...
... In fact, activated astroglia and microglia surround the amyloid deposits and neuritic plaques in the brain of AD patients [54]. ...
... Categorization has thus relied on transient markers or inhibitor efficacy in cultured cells. This is not feasible in humans, in which retrospective extrapolation has revealed a substantial contribution of non-apoptotic cell death in stroke [1], Alzheimer's [2], Parkinson's [3], and Huntington's [4] disease, necessitating identification of reliable biomarkers of cell death processes in these diseases. ...
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... Leptomeninges and large cortical blood vessels were collected by sieving through a 75-m mesh. Subsequent digestion in 0.1% collagenase, 0.025% elastase, and 0.04% hyaluronidase (Sigma) for 45 min at 37ЊC, as previously described for canine and human cells (20)(21)(22)(23), liberated vascular smooth muscle cells. ...
