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PubMed2000

[Non-steroidal anti-inflammatory drugs with selectivity for cyclooxygenase-2 in Alzheimer's disease. Rationale and perspectives].

POSSIBLE INFLAMMATORY MECHANISMS: Alzheimer's disease (AD) is a degenerative disease of the brain including possibly inflammatory mechanisms, as illustrated by the presence of activated microglial cells in the periphery of senile plaques and neurofibrillary tangles and the subsequent release of proinflammatory mediators with neurotoxic potency. RATIONALE FOR NSAID USE: Although not firmly demonstrated, the rationale for the prescription of non steroidal anti-inflammatory drugs (NSAIDS) as neuroprotective agents in AD lies on epidemiological data having shown a reduced risk of developing AD in patients on long-term therapy with NSAIDs (non selective cyclo-oxygenase [COX] inhibitors). RATIONALE FOR THE USE OF SELECTIVE COX-2 INHIBITORS: The rationale for the prescription of selective COX-2 inhibitors as neuroprotective drugs in AD lies on: Epidemiological data having shown a reduced risk of developing AD in patients treated with anti-inflammatory doses of classical NSAIDs (inhibition of COX-1 and COX-2) but not with antithrombotic doses of aspirin (selective inhibition of COX-1), Cellular experiments, Demonstration of a better gastro-intestinal (GI) safety profile with selective COX-2 inhibitors than with classical NSAIDs in short-term studies, allowing a possible long-term use in AD. BEFORE PRESCRIBING: COX-2 may have an ambivalent functionality in the brain since the basal production of prostaglandins through COX-2 may participate in neuronal homeostasis whereas the expression of COX-2 is associated with brain development. Classical NSAIDs are ineffective in reducing the formation of senile plaque and neurofibrillary tangles in AD, which is consistent with an ability to reduce inflammation associated with activation of microglia but illustrates their failure to suppress the degenerative process. Prophylactic use of selective COX-2 NSAIDs can be considered on the basis of their good GI safety after 6 months of marketing in United States but need to be confirmed for a longer time. CURRENT TRIALS: Clinical studies focusing on both the prevention and the slowing down of early AD are under way with two recently launched selective COX-2 inhibitors, celecoxib and rofecoxib.

Adult↗

PubMed1987

Cortical neuropathological and neurochemical substrates of Alzheimer's and Parkinson's diseases.

Whilst the neuropathological correlates of Alzheimer type dementia--cortical neurofibrillary tangles and senile plaques--are well defined, the prevalence of these cortical abnormalities in Parkinson's disease and their relation to dementia is unclear. In a series of 46 consecutive cases of clinically and pathologically established Parkinson's disease the prevalence of mild Alzheimer-type pathology (exceeding the normal but not as extensive as in Alzheimer's disease) was increased 2 to 3 fold compared with an age-matched control group, although there was no obvious relation to the presence or severity of dementia. In a subgroup of Parkinsonian cases (both demented and non-demented), examined neurochemically, there were both similarities (decreased choline acetyltransferase, nicotinic and serotonergic S 1 receptor activities) and distinctions (increased muscarinic receptor binding--particularly to the "L" subtype, and normal serotonergic S 2, somatostatin, and D-aspartate binding together with normal levels of an endogenous nicotine binding inhibitor) compared with a group of cases with Alzheimer's disease. Amongst the various pathological and chemical indices examined, only presynaptic cholinergic markers (including the number of Meynert neurons) and S 1 receptor binding were related to dementia in Parkinson's disease. It is suggested that whilst coincidental classical Alzheimer's disease is infrequent in Parkinson's disease (5% in the present series) Alzheimer's disease itself is distinguished from Parkinson's disease by the formation of numerous neocortical neurofibrillary tangles and a reduction in glutamate uptake, serotonergic S 2 receptors and possibly in endogenous nicotine binding inhibitor.

Adult↗

PubMed2002

Clinical features and changing patterns of neurodegenerative disorders on Guam, 1997-2000.

BACKGROUND: In the 1950s, high-incidence ALS and Parkinson-dementia complex (PDC) were identified among Chamorros, the native inhabitants of Guam. Brains of patients with these syndromes showed widespread neurofibrillary tangles. Although ALS and PDC were reported to have dramatically declined in the 1980s, new cases are still encountered. Late-life dementia has received little study among Chamorros. METHODS: From 1997 to 2000, the authors evaluated newly referred and previously identified patients. They screened first-degree relatives of previous registries, and subjects aged 60 or older. Subjects who scored below a cognitive test cutoff or had symptoms or signs consistent with parkinsonism or ALS underwent psychometric testing, assessment by a neurologist, and laboratory studies as appropriate. Consensus diagnoses were made. RESULTS: The authors identified 194 Chamorros with ALS (n = 10), PD (n = 11), PDC (n = 90), or late-life dementia (n = 83). Mean ages at onset were 55 for ALS, 68 for PDC, 63 for PD, and 74 for dementia. Late-life dementia was more common in women, and met criteria for probable or possible AD. The APOE-epsilon 4 allele frequency was uniformly low regardless of neurologic diagnosis. CONCLUSIONS: The rapid decline of high-incidence ALS on Guam over the past 40 years suggests the contribution of a modifiable environmental factor. PDC remains relatively common, with an unchanged clinical picture apart from later age at onset. Dementia among elderly Chamorros (termed "Mariana dementia") resembles AD. Autopsy studies will clarify whether this dementia is related to AD pathology or represents a late-life neurofibrillary tangle syndrome more closely allied to PDC.

Age of Onset↗

PubMed2005

Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies.

Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK/JNK and p38 and hyperphosphorylated tau containing neurites have been observed around betaA4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that betaA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-beta immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.

Alzheimer Disease↗

PubMed2005

Interaction of stress proteins with misfolded keratins.

Misfolded and aggregated proteins are a characteristic feature of a variety of chronic diseases. Examples include neurofibrillary tangles in Alzheimer disease, Lewy bodies in Parkinson disease and Mallory bodies (MBs) in chronic liver diseases, particularly alcoholic and non-alcoholic steatohepatitis (ASH and NASH). MB formation is at least in part the result of chronic oxidative cell stress in hepatocytes and can be induced in mice by long-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Proteomic analysis revealed that MBs consist of ubiquitinated keratins and the stress proteins Hsp70, Hsp25, and p62. Furthermore, marked overexpression of clusterin, which shares functional properties with small heat shock proteins, was identified by gene expression profiling of DDC-treated mice livers. To investigate whether clusterin has a function in the stress response to misfolded keratins, we performed transfection studies utilizing expression constructs encoding ubiquitin, p62, Hsp27, clusterin, keratin 8, and keratin 18. Ubiquitin was found in a strong and constant association with keratin aggregates, whereas binding of p62 to keratin was variable. Hsp27 did not colocalize with keratin aggregates under these experimental conditions. In contrast, clusterin associated with misfolded keratin only if its signal peptide was deleted and its secretion inhibited. This suggests that clusterin has ability to bind misfolded proteins, including keratins but its physiological function is restricted to the extracellular space. The extracellular localization of clusterin was underlined by immunohistochemical studies in Alzheimer disease brains, where clusterin was constantly found in association with amyloid plaques; in contrast, cytoplasmic inclusions such as neurofibrillary tangles as well as MBs in ASH were negative. Furthermore, we found clusterin in association with elastic fibers in the extracellular matrix in several chronic liver diseases, including ASH and alpha1-antitrypsin deficiency, implying a possible role of clusterin in liver fibrosis.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice.

BACKGROUND: Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by a temporal and spatial progression of beta-amyloid (Abeta) deposition, neurofibrillary tangle formation, and synaptic degeneration. Inflammatory processes have been implicated in initiating and/or propagating AD-associated pathology within the brain, as inflammatory cytokine expression and other markers of inflammation are pronounced in individuals with AD pathology. The current study examines whether inflammatory processes are evident early in the disease process in the 3xTg-AD mouse model and if regional differences in inflammatory profiles exist. METHODS: Coronal brain sections were used to identify Abeta in 2, 3, and 6-month 3xTg-AD and non-transgenic control mice. Quantitative real-time RT-PCR was performed on microdissected entorhinal cortex and hippocampus tissue of 2, 3, and 6-month 3xTg-AD and non-transgenic mice. Microglial/macrophage cell numbers were quantified using unbiased stereology in 3xTg-AD and non-transgenic entorhinal cortex and hippocampus containing sections. RESULTS: We observed human Abeta deposition at 3 months in 3xTg-AD mice which is enhanced by 6 months of age. Interestingly, we observed a 14.8-fold up-regulation of TNF-alpha and 10.8-fold up-regulation of MCP-1 in the entorhinal cortex of 3xTg-AD mice but no change was detected over time in the hippocampus or in either region of non-transgenic mice. Additionally, this increase correlated with a specific increase in F4/80-positive microglia and macrophages in 3xTg-AD entorhinal cortex. CONCLUSION: Our data provide evidence for early induction of inflammatory processes in a model that develops amyloid and neurofibrillary tangle pathology. Additionally, our results link inflammatory processes within the entorhinal cortex, which represents one of the earliest AD-affected brain regions.

Journal Article↗

PubMed1997

Distribution of the messenger RNA for the extracellularly regulated kinases 1, 2 and 3 in rat brain: effects of excitotoxic hippocampal lesions.

Neurofibrillary tangles in Alzheimer's disease are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Based on biochemical criteria, several enzymes have emerged as potential tau protein kinases, including the extracellularly regulated kinases 1, 2 and 3. In situ hybridization was used to map the messenger RNA distribution of extracellularly regulated kinase 1, 2 and 3 in the adult rat brain and their response to excitotoxic hippocampal lesions was examined. Extracellularly regulated kinase 1 messenger RNA was uniformly expressed by glia, but was also present in the dentate gyrus and some other neuronal populations. Extracellularly regulated kinase 2 was exclusively neuronal and concentrated within the cortical laminae and the CA subfields of the hippocampal formation. Extracellularly regulated kinase 3 messenger RNA expression was similar to extracellularly regulated kinase 2 and was also present in neurons but the level of expression was lower. Extracellularly regulated kinases 2 and 3 messenger RNA expression was lost following excitotoxic injury, further supporting a neuronal localization. Extracellularly regulated kinase 1 messenger RNA expression appeared unaltered, suggesting a non-neuronal localization and lack of responsiveness to lesion at the level of transcription. By contrast, messenger RNA of sgk, a recently described serine/threonine kinase, was up-regulated by glial cells following excitotoxic injury. Based on their messenger RNA distribution, cellular localization and response to lesion, it is clear that each kinase may function differently in various signaling pathways. Extracellularly regulated kinase 2, however, is the only kinase with the proper messenger RNA distribution to contribute to neurofibrillary tangle formation in Alzheimer's disease.

Animals↗

PubMed2000

Avoidance of Apoptosis in Alzheimer's Disease.

Internucleosomal DNA fragmentation, which is a well-known feature of apoptosis but not an absolute criterion for identifying apoptosis (1), has often been observed in the brain tissue of Alzheimer's disease (AD). However, classical apoptotic morphology such as nuclear condensation, membrane blebbing and apoptotic bodies are seldom seen in AD brain. In this issue of Journal of Alzheimer's Disease, Velez-Pardo et al. have reported the DNA fragmentation using terminal dUTP labeling (TUNEL) in postmortem brains of familial AD with presenilin-1 [E280A] mutation. Importantly, no classical apoptotic morphology has been observed also in the brains of presenilin-1 familial AD. Furthermore, Velez-Pardo et al. have shown that there is no obvious correlation between DNA fragmentation and the severity of amyloid deposition as well as between DNA fragmentation and the severity of neurofibrillary tangle formation. An apoptotic pathway only takes several hours or at most a few days for completion. In the development of the lateral motor column of the chick embryo, 8,000 cells out of 20,000 cells die, i.e. loss of 40% of the population occurs within 3 days (2). The fact that only 5% of the population in the lateral motor column is undergoing apoptosis at any particular time in this period (2) indicates that apoptotic pathway requires about 10 hours for completion. In a striking contrast with the physiologically programmed cell death, loss of 40% of the population occurs (3,000 neurons out of 7,000 neurons per 50 micron-thick section are lost) within 10 years in the temporal cortex neurons of AD (3). If we suppose that 20-40% of neurons of the temporal cortex are undergoing degeneration at any given time in the course of AD, an individual neuron in the temporal cortex of AD requires 5-10 years to die. Indeed, we can observe neurons displaying many of the features of apoptosis in AD. This fact argues that neurons in AD have mounted an effective defense to apoptotic death (an avoidance of apoptosis) rather than actual completion of apoptosis (4,5). It is noteworthy that nucleic acid oxidation occurs widely in vulnerable neuronal populations in AD (6) and oxidative damage can directly cause DNA fragmentation (7). Therefore, DNA damage possibly resulting from oxidative stress involves vulnerable neurons in AD beyond the distribution of amyloid deposition or neurofibrillary tangles, which may be related to neuronal cell death occurring independently of the classical AD pathology (3).

Journal Article↗

PubMed2006

Interleukin-1 mediates Alzheimer and Lewy body pathologies.

BACKGROUND: Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is now well recognized. Such cases of concurrent AD and Lewy body disease (AD/LBD) show neuropathological changes that include Lewy bodies (alpha-synuclein aggregates), neuritic amyloid plaques, and neurofibrillary tangles (hyperphosphorylated tau aggregates). The co-occurrence of these clinical and neuropathological changes suggests shared pathogenic mechanisms in these diseases, previously assumed to be distinct. Glial activation, with overexpression of interleukin-1 (IL-1) and other proinflammatory cytokines, has been increasingly implicated in the pathogenesis of both AD and PD. METHODS: Rat primary cultures of microglia and cortical neurons were cultured either separately or as mixed cultures. Microglia or cocultures were treated with a secreted fragment (sAPPalpha) of the beta-amyloid precursor protein (betaAPP). Neurons were treated with IL-1beta or conditioned medium from sAPPalpha-activated microglia, with or without IL-1 receptor antagonist. Slow-release pellets containing either IL-1beta or bovine serum albumin (control) were implanted in cortex of rats, and mRNA for various neuropathological markers was analyzed by RT-PCR. Many of the same markers were assessed in tissue sections from human cases of AD/LBD. RESULTS: Activation of microglia with sAPPalpha resulted in a dose-dependent increase in secreted IL-1beta. Cortical neurons treated with IL-1beta showed a dose-dependent increase in sAPPalpha release, an effect that was enhanced in the presence of microglia. IL-1beta also elevated the levels of alpha-synuclein, activated MAPK-p38, and phosphorylated tau; a concomitant decrease in levels of synaptophysin occurred. Delivery of IL-1beta by slow-release pellets elevated mRNAs encoding alpha-synuclein, betaAPP, tau, and MAPK-p38 compared to controls. Finally, human cases of AD/LBD showed colocalization of IL-1-expressing microglia with neurons that simultaneously overexpressed betaAPP and contained both Lewy bodies and neurofibrillary tangles. CONCLUSION: Our findings suggest that IL-1 drives production of substrates necessary for formation of the major neuropathological changes characteristic of AD/LBD.

Journal Article↗

PubMed2001

[An autopsied case of presenile dementia with tangles].

We report an autopsied case of presenile dementia showing neuropathologically abundant neurofibrillary tangles(NFT) without senile plaques(tangle only dementia). A Japanese woman developed memory disturbance when she was 60 years old. At age of 65, her ability to understand deteriorated and euphoria and wandering manifested but neither psychotic symptoms, including hallucination and delusion nor a change in character were observed. The patient was hospitalized at age 66 and a cranial CT scan revealed bilateral moderate atrophy of the cortex and moderate enlargement of the lateral ventricle, especially in the inferior horn. No lobar atrophy was detected. She exhibited an oral tendency and became appallic at her final stage and died at the age of 75. Autopsy showed that her brain weighed 850 g and neuropathological study showed numerous NFT mainly in the entorhinal (trans-entorhinal) region, subiculum, CA1-CA4, dentate gyrus, amygdara, subthalamic nucleus, basal nucleus of Meynert, substantia nigra and locus coeruleus. Severe neuronal loss with gliosis was noted in the temporal lobes including the hippocampal region. No senile plaque was detected in any of the brain regions. There have been some recent reports of patients with abundant NFT with the predominant involvement of the allocortex but no or very little senile plaque. All the patients in the reported cases were very elderly at onset(over 80 years of age). In our case, the onset was presenile and we could exclude any other diseases, that usually present with NFT, and to our knowledge, this is the first report of a presenile dementia with tangles.

Aged↗

PubMed2001

Where do Alzheimer's plaques and tangles come from? Aging-induced protein degradation inefficiency.

Amyloid plaques and neurofibrillary tangles are prominent lesions in the aging brain and they may be responsible for cell death in Alzheimer's disease. But a basic question has not been answered: why and how are plaques and tangles formed during aging? In this study, we approach this question by first examining what happens in the aging body. Plaques and tangles do not come alone, but together with many other aging markers in the body (cholesterol deposition, gallstones, hair graying, and bone loss, etc.). Because these aging markers occur to a certain extent in all elderly and at about the same time in life, it is reasonable to conceive that they originate from a common cause, that is, aging-induced metabolic inefficiency. If cholesterol and gallstone depositions are the results of inefficient degradation/clearance of lipids and minerals, then similarly plaque and tangle formation in most people would be the results of inefficient normal degradation of ?-amyloid precursor protein (APP) and tau, respectively. By this view, our studies should focus on the enzymes responsible for APP and tau normal degradation and their natural changes in aging, rather than on presumed pathological factors. Whatever precise mechanisms underlying their depositions, plaques and tangles are the natural products of aging, thus fundamentally different from pathological events such as cancer growth in concept.

Aging↗

PubMed1991

Aluminum, Alzheimer's disease, and the olfactory system.

In Alzheimer's disease, it has been recognized that there is a dramatic tendency for the development of neurofibrillary tangles among neurons of cortical regions associated with the olfactory system. We have demonstrated that neurofibrillary tangle-bearing neurons contain dramatically elevated levels of aluminum. The olfactory system, the only portion of the central nervous system with exposure to the external environment, is uniquely capable of uptake and transneuronal spread of exogenous substances. We argue that inasmuch as aluminum is not employed in any physiologic process, these deposits must arise from exogenous sources. Using parkinsonism-dementia complex of Guam as a model, we present data which suggest that the olfactory system is particularly vulnerable to damage and is affected very early in the disease. This supports the concept that etiologic agents of importance to this epidemic may be airborne in nature and may enter the central nervous system via the olfactory pathways.

Aluminum↗

PubMed1994

The solubilization of model Alzheimer tangles: reversing the beta-sheet conformation induced by aluminum with silicates.

Neurofibrillary tangles are one of two lesions found in the brain of Alzheimer disease victims. With synthetic peptide fragments of human neurofilament NF-M17 (Glu-Glu-Lys-Gly-Lys-Ser-Pro- Val-Pro-Lys-Ser-Pro-Val-Glu-Glu-Lys-Gly, phosphorylated and unphosphorylated), CD studies were done to examine the effect of sodium orthosilicate on the conformational state produced by Al3+ on fragments of neuronal proteins. Previous studies had shown a conformational transition from alpha-helix and random to beta-pleated sheet upon addition of Al3+ to both phosphorylated and unphosphorylated peptides. If sufficient quantities of Al3+ are added, the peptide precipitates from solution. The ability to reverse or slow the progression of aggregation was examined. Al3+ binding was reversed with 1-2 molar equivalents of sodium orthosilicate (with respect to Al3+), altering the conformation from beta-sheet to random coil and resulting in a CD spectrum similar to that of the initial peptide. The tight binding of the SiO4(4-) with the Al3+ provides the mechanism for this transition. These results provide additional information toward understanding the role of aluminum in the Alzheimer diseased brain and suggest the investigation of the possible use of silicates as a therapeutic agent.

Aluminum↗

PubMed1999

Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease.

The distribution and density of neurofibrillary tangles and amyloid plaques was studied in a unique series of cases whose premortem cognitive status had been assessed with the Clinical Dementia Rating (CDR), including 39 nondemented cases (CDR = 0; age, 51-88 years), 15 very mildly demented cases (CDR = 0.5), and 8 severely demented (CDR = 3) cases. The initial formation of tangles and plaques in healthy aging appeared to be independent of each other. Tangles were found in all the nondemented cases, especially in hippocampal and parahippocampal areas; the average tangle concentration increased exponentially with age. In contrast, plaques were absent in some brains up to age 88, and the earliest plaque formation in other cases occurred in the neocortex, in patches of diffuse plaques. Widely distributed neuritic as well as diffuse plaques throughout neocortex and limbic structures characterized a further group of nondemented cases. In these cases there was also a substantial increase over other nondemented cases, both in the number of tangles and in the rate of increase in tangles with age, suggesting an interaction between amyloid and neurofibrillary change at this stage. Such cases closely resemble CDR = 0.5 cases, and it is proposed they represent "preclinical" Alzheimer's disease.

Age Distribution↗

PubMed1992

Perisomatic sprouts immunoreactive for nerve growth factor receptor and neurofibrillary degeneration affect different neuronal populations in the basal nucleus in patients with Alzheimer's disease.

Aberrant morphological profiles, most likely reflecting a process of perisomatic sprouting, have been detected in Alzheimer's disease (AD) on neurons of the basal nucleus of Meynert by means of Golgi impregnation. Using the mouse monoclonal antibody, ME 20.4., perisomatic profiles were shown to be immunoreactive for nerve growth factor receptor (NGFR). Double label studies using either thioflavin S or anti-neurofibrillary tangle (NFT) antibody B5 in combination with ME 20.4 demonstrated that neurons with aberrant growth profiles failed to express neurofibrillary tangle-bearing material, which otherwise could be detected in large amounts throughout the basal forebrain. The results indicate that in AD, neurons in the basal forebrain, not affected by neurofibrillary degeneration, respond to an increased trophic influence. Dendritic sprouting in AD might, therefore, more likely be regarded as an attempt by the nervous system to repair itself following damage rather than as an abnormal process with primary pathologic significance leading to cellular degeneration.

Aged↗

PubMed1985

Substructure of 20 nm filaments of progressive supranuclear palsy.

In contrast to the ultrastructure of Alzheimer's neurofibrillary tangles (NFT), which has been well characterized as accumulations of paired helical 10-nm filaments (PHF) with 80-nm regular constrictions, the morphology of the neurofibrillary changes of PSP remains ill-defined. Until recently, the fine structure of PSP tangles was generally accepted as 15-nm straight filaments or tubules, although many reports describing different electron-microscopic findings have appeared in the literature. In this report, we present morphological data indicating a protofilamentous substructure present in straight filaments of PSP which has some points of similarity with the protofilamentous architectures which have been reported for paired helical filaments of Alzheimer's disease. The straight filaments were found to be composed of six or more helically symmetric 2-5-nm protofilaments. We conclude that despite the varied morphology of filaments in neurofibrillary tangles observed in PSP there may be some underlying identity at the molecular level with the PHF of neurofibrillary tangles of Alzheimer's disease.

Aged↗

PubMedDate not supplied

The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease.

Neurofibrillary tangles and senile plaques, together with cells immunoreactive for the Alz-50 antibody (A50-ir cells) or for an antibody against paired helical filaments (PHF-ir cells), and amyloid deposits stained with antibodies against beta-(or A4)-amyloid, have been mapped throughout the ventral forebrains of 25 old people. The cognitive status of each individual was assessed and a "Clinical Dementia Rating" (CDR) assigned, either before death in the Memory and Aging Project of Washington University, or by a postmortem interview, with an appropriate collateral source. The cases studied included 13 nondemented cases (CDR = 0), six very mildly to mildly demented cases (CDR = 0/0.5 to 1) and six more severely demented cases (CDR = 2 to 3). Because even the very mildly demented brains showed substantial pathological change, emphasis was placed on examining the nondemented cases for the earliest changes that could be associated with Alzheimer's disease. Different distributions were found for tangles and plaques. Tangles (and A50-ir and PHF-ir cells) were present in all of the brains examined. In the younger nondemented cases (aged 54 to 63) there were a few affected cells in the anterior olfactory nucleus and the parahippocampal gyrus. In older nondemented cases (aged 73-89) more tangles were found in the same areas, and also in hippocampal field CA1. The very mildly demented cases had many more tangles, but their distribution was similar. Only in the severely demented cases were large numbers of tangles present in the neocortex. In contrast, no plaques (or beta-amyloid immunoreactivity) were found in any of the younger nondemented cases or in four of the eight older nondemented cases. In three older nondemented cases there were a few primitive plaques, which were restricted to localized regions of the neocortex (e.g., a portion of the inferior temporal cortex). In one nondemented case and all of the very mildly to mildly demented cases there were very large numbers of mostly primitive plaques, particularly in the neocortex. With greater severity of dementia there is a shift from primitive to mature plaques. These results were interpreted to imply that the first development of tangles and plaques occurs in different parts of the brain. Tangles appear during aging in the anterior olfactory nucleus, the parahippocampal gyrus and the hippocampus, but are rare in the neocortex except in demented brains. Conversely plaques may develop first in the neocortex. Unlike tangles, plaques are not a consistent feature of aging, at least up to age 80.

Aged↗

PubMed2003

Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease.

BACKGROUND: Most patients with dementia with Lewy bodies (DLB) exhibit diffuse plaque-only pathology with rare neocortical neurofibrillary tangles (NFTs), as opposed to the widespread cortical neurofibrillary-tau involvement in Alzheimer disease (AD). Another pathological difference is the astrocytic and microglial inflammatory responses, including release of interleukins (ILs), around the neuritic plaques and NFTs in AD brains that are absent or much lower in DLB. We analyzed cerebrospinal fluid (CSF) markers that reflect the pathological differences between AD and DLB. OBJECTIVE: To determine CSF concentrations of tau, beta-amyloid, IL-1beta, and IL-6 as potential diagnostic clues to distinguish between AD and DLB. METHODS: We measured total tau, beta-amyloid1-42, IL-1beta, and IL-6 levels in CSF samples of 33 patients with probable AD without parkinsonism, 25 patients with all the core features of DLB, and 46 age-matched controls. RESULTS: Patients with AD had significantly higher levels of tau protein than patients with DLB and controls (P<.001). The most efficient cutoff value provided 76% specificity to distinguish AD and DLB cases. Patients with AD and DLB had lower, but not significantly so, beta-amyloid levels than controls. The combination of tau and beta-amyloid levels provided the best sensitivity (84%) and specificity (79%) to differentiate AD vs controls but was worse than tau values alone in discriminating between AD and DLB. Beta-amyloid levels had the best correlation with disease progression in both AD and DLB (P =.01). There were no significant differences in IL-1beta levels among patients with AD, patients with DLB, and controls. Patients with AD and DLB showed slightly, but not significantly, higher IL-6 levels than controls. CONCLUSIONS: The tau levels in CSF may contribute to the clinical distinction between AD and DLB. Beta-amyloid CSF levels are similar in both dementia disorders and reflect disease progression better than tau levels. Interleukin CSF concentrations do not distinguish between AD and DLB.

Aged↗