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PubMed1998

Alzheimer's disease. The density of amygdalar neuritic plaques is associated with the severity of neurofibrillary pathology and the degree of beta-amyloid protein deposition in the cerebral cortex.

The gradual development of Alzheimer-related neurofibrillary changes and beta-amyloid deposits have been investigated in the amygdala and cerebral cortex with advanced silver methods. Neurofibrillary tangles occur within the somata of nerve cells, while neuropil threads are located in nerve cell processes. In neuritic plaques, there are both neuronal processes containing neurofibrillary changes and extracellular deposits of beta-amyloid protein. The amygdala early displays Alzheimer-type pathology and is typically rich in neuritic plaques. Neuritic plaques do not occur in the amygdala in the absence of neuropil threads and neurofibrillary tangles in the entorhinal region and amygdala. In contrast to the gradual increase in the number of neurofibrillary tangles and neuropil threads, neuritic plaques grow in size and number along with advancement in the neurofibrillary and beta-amyloid pathology. The findings indicate that neuropil threads and neurofibrillary tangles in the entorhinal region and amygdala precede neuritic plaques in the amygdala, and the density of neuritic plaques is related both to the degree of neurofibrillary and beta-amyloid pathology in the cerebral cortex.

Adult↗
PubMed1994

[A correlative study of the aluminum content and aging changes of the brain in non-demented elderly subjects].

The interrelation of the aluminum content and aging change of the nerve cells was studied with special reference to the neurofibrillary tangle (NFT) and occurrence of senile plaque (SP), in 15 autopsied brains (cerebrum) of non-demented elderly subjects varying in age from 75 to 101 years old and 10 cases of non-demented non-elderly adult subjects. 1) In the brain of non-demented non-elderly adult subjects, the aluminum content of the hippocampus was 14.4 +/- 1.39 ppb and that of the cortex of the frontal lobe was 20.4 +/- 2.54 ppb. In the brain of the non-demented elderly subjects, the aluminum content of the hippocampus was 401.7 +/- 60.05 ppb and that of the cortex of the frontal lobe was 373.29 +/- 72.35 ppb. Comparison of the two groups showed obviously higher levels in the latter group, being 28 times in the hippocampus and 19 times in the cortex of the frontal lobe. 2) The histochemical demonstration of the aluminum localization by the Morin method disclosed the positive fluorescence reaction along the part of the disintegrating neurofibrillary tangle and amyloid core in the senile plaques of non-demented elderly subjects. In the normal brain tissue, positive fluorescence reaction was observed in the wall of the capillary vessels of the blood brain barrier, perivascular glial supporting tissues, the nuclei of the astrocytes and nuclei, nucleoli of the nerve cells partially. No fluorescence reaction was observed in the non-demented adult subjects. 3) Morphologically, the appearance of the neurofibrillary tangle was noted in some cases of non-demented elderly group with higher aluminum levels. Classical and diffuse type senile plaques were dispersed in the 1st to 4th zone of the cortex of the frontal lobe. However, diffuse type senile plaques in the hippocampus appeared to a lesser extent. Neurofibrillary tangles were slightly noted in the cortex of the frontal lobe, however marked increase was confirmed in the CA1 to CA3 zones of the hippocampus. Ultrastructurally, paired helical filaments (PHF) were noted in the neurofibrillary tangle constituent and the increase of amyloid fibrils in senile plaques was confirmed. In this study, high levels of the aluminum content of the brain were confirmed in the non-demented elderly subjects. Moreover, the histochemical demonstration of aluminum localization by the Morin method disclosed a positive fluorescence reaction along the sites of neurofibrillary tangles and amyloid core in the senile plaques of non-demented elderly subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1992

Localization of heparan sulfate glycosaminoglycan and proteoglycan core protein in aged brain and Alzheimer's disease.

Two monoclonal antibodies, one which recognizes a glycosaminoglycan epitope present in heparan sulfate glycosaminoglycan and another which recognizes the core protein of a basement membrane heparan sulfate proteoglycan, were used to study the distribution and localization of these components in Alzheimer's disease and control brain. The cytoplasm of neurons, and occasional neurofibrillary tangles, senile plaques and astrocytes were immunopositive for the heparan sulfate glycosaminoglycan antibody in control brains. In Alzheimer's tissue, however, the number and intensity of these elements was more extensive than in control brains. In addition, within the Alzheimer's brains studied, the nuclei of select neurons and a small number of microglia were also immunopositive for heparan sulfate glycosaminoglycan in contrast to controls, where nuclei and neuroglia were immuno-negative. Some senile plaques in Alzheimer's tissue also contained strong heparan sulfate glycosaminoglycan-positive neurites which were not seen in controls. In Alzheimer's tissue, double labeling for heparan sulfate glycosaminoglycans and the beta-amyloid protein in adjacent sections revealed that, in general, heparan sulfate glycosaminoglycan- and beta-amyloid protein-immunopositive plaques were co-localized. Occasionally, however, beta-amyloid-positive plaques were seen without heparan sulfate glycosaminoglycan immunoreactivity and vice versa. Heparan sulfate glycosaminoglycan immunoreactivity and Tau immunoreactivity co-localized in many neurofibrillary tangles; however a small number of heparan sulfate glycosaminoglycan-positive neurofibrillary tangles did not co-localize with Tau-positive neurofibrillary tangles. In contrast, the heparan sulfate proteoglycan antibody immunostained only the walls of blood vessels and a few senile plaques in Alzheimer's brains and primarily blood vessels in control brains. Heparan sulfate glycosaminoglycan immunostaining was present within neurons, glia, neurofibrillary tangles and senile plaques in Alzheimer's tissue. These results suggest that heparan sulfate-like molecules play an important role in the pathogenesis of the characteristic lesions of Alzheimer's disease and could serve as a marker reflecting early pathological changes.

Aged↗
PubMed1989

Cationic dyes reveal proteoglycans structurally integrated within the characteristic lesions of Alzheimer's disease.

The cationic dyes ruthenium red (RR) and cuprolinic blue (CB) were used to preserve proteoglycans (PGs) for visualization at the ultrastructural level in brain tissue from seven cases of Alzheimer's disease (obtained at autopsy within 3-4 h after death). PGs were visualized as RR-positive granules specifically localized to the amyloid fibrils in neuritic plaques. In neurofibrillary tangles, RR granules were localized to the paired helical filaments and straight filaments usually at a consistent periodicity of 40-70 nm. CB, known to preserve PGs as short punctate filaments, also demonstrated PGs specifically localized to the amyloid fibrils in neuritic plaques and in association with paired helical filaments and straight filaments in neurofibrillary tangles. Persistent staining with CB at magnesium chloride concentrations of 0.3 and 0.7 M in the neuritic plaques suggested the presence of highly sulfated PGs, whereas abolishment of CB staining at 0.7 M magnesium chloride in the neurofibrillary tangles implied that different PGs and/or glycosaminoglycans were present in the neurofibrillary tangles. The specific ultrastructural localization of PGs to the characteristic lesions in Alzheimer's disease suggests that PGs are part of a complex structural network with amyloid fibrils in neuritic plaques and the filamentous structures present in neurofibrillary tangles.

Alzheimer Disease↗
PubMed1985

Paired helical filaments from Alzheimer disease patients contain cytoskeletal components.

Neurofibrillary tangles from Alzheimer disease patients share antigenic determinants with neurofilaments and microtubule-associated proteins, as shown by light microscopy immunocytology. The present study addresses the issue of whether these determinants are located on the paired helical filaments or on other components of the neurofibrillary tangle. Sections from postmortem brains from Alzheimer disease patients were stained by using Bodian's silver method or immunostained by using poly- and monoclonal antibodies to neurofilaments and polyclonal antibodies to microtubules. Bodian's silver stain has an intense affinity for neurofibrillary tangles and has been shown to bind to specific domains of neurofilament subunits. The antibodies to neurofilaments used here immunostain most or all of the neurofibrillary tangles present in the sections whereas the antiserum to microtubule protein immunoreacted with about half of the neurofibrillary tangles. All of the antibodies as well as Bodian's silver stain reacted with the paired helical filaments. The epitopes that we have shown to be present in the paired helical filament, in contrast to the corresponding epitopes present in normal neuronal cytoskeleton, are insoluble in ionic detergent. It is concluded that these epitopes are integral components of the paired helical filaments and that, at least in part, paired helical filaments are derived from altered elements of the normal neuronal cytoskeleton.

Aged↗
PubMed2006

Alzheimer's disease and frontotemporal dementia: prospects of a tailored therapy?

Alzheimer's disease (AD) is the most prevalent dementia (accounting for 50%-75% of cases of dementia in people aged over 65 years), followed by frontotemporal dementia (FTD) (10%-20% of cases). AD is characterised histopathologically by Abeta-containing amyloid plaques and tau-containing neurofibrillary tangles, whereas FTD exhibits neurofibrillary tangles alone. Current symptomatic treatments of AD are of limited benefit, as they are not directed at the underlying biological basis of the disease. The development of transgenic animal models has provided insight into disease mechanisms and helped define novel drug targets. More than 50 drugs are currently in clinical trials, and novel and more effective drugs targeting both AD and FTD are expected to become available within 5-10 years.

Alzheimer Disease↗
PubMedDate not supplied

The amyloid peptide and its precursor in Alzheimer's disease.

Alzheimer's disease, the most frequent cause of dementia, is characterized by the formation in the brain of neurofibrillary tangles and senile plaques. Neurofibrillary tangles are composed of bundles of paired helical filaments containing the microtubule-associated protein tau. In autopsy-derived brain samples from patients with Alzheimer's disease, tau is hyperphosphorylated and constitutes a promising disease marker. Senile plaques contain a small amyloid peptide derived from the amyloid precursor protein. Mutations of the amyloid precursor protein gene have been identified in rare cases of familial Alzheimer's disease, suggesting a causal role for amyloid peptide deposition in the disease. However, Alzheimer's disease has been demonstrated to be characterized by an important genetic heterogeneity. The identification of pathogenic DNA mutations, different from those of the amyloid precursor protein gene, will reveal whether the corresponding genes are involved in either an increased production of the amyloid peptide or a decrease of its removal, or in the fibrillogenic properties of the peptide, which seem to be related to its toxicity. Several mammalian cells are able to produce the amyloid peptide from its precursor. Understanding the cellular mechanisms that determine how cleavages occur in cells could help to identify new strategies for modulating amyloid peptide production. In attempts to produce animal models of Alzheimer's disease, investigators have used transgenic strategies. To date, these efforts have not been very successful. However, the expression in transgenic mice of both mutated amyloid peptide precursor and amyloid associated proteins should prove useful for examining the importance of putative etiological factors, and for testing novel therapies including anti-amyloidogenic strategies.

Aged↗
PubMed2000

A role for the substantia nigra pars reticulata in the gaze palsy of progressive supranuclear palsy.

We examined the topography and degree of cell loss within basal ganglia structures commonly involved in progressive supranuclear palsy in order to identify any relationship between degeneration in these nuclei and gaze palsy. Serial section analyses and unbiased quantitative techniques were applied to brain tissue from six cases with progressive supranuclear palsy (four with gaze palsy and two without) and six controls with no neurological or neuropathological abnormalities. The total number of nucleolated neurons within the substantia nigra pars compacta (SNc) and reticulata (SNr), the subthalamic nucleus, and the internal and external segments of the globus pallidus was determined for all subjects and the data expressed as percentages of control values to compare degeneration across these basal ganglia structures. The density of neurofibrillary tangles was also evaluated within these structures. Despite significant subcortical neurofibrillary tangle formation in all cases, there was considerable variability in the degree of neuronal cell loss in all basal ganglia regions, except the SNc which was consistently affected. There was no correlation between the ranked density of neurofibrillary tangles and the degree of neuronal cell loss in any basal ganglia region. Comparisons between cases with and without gaze palsy revealed a 40% greater decrease in the number of SNr neurons in cases with gaze palsy (75 +/- 8% loss) compared with those without (35 +/- 14% loss). This was the largest difference between these cases. As the SNr projects to the superior colliculus, degeneration of this basal ganglia structure may disrupt eye movements in progressive supranuclear palsy.

Aged↗
PubMed1991

Neuritic pathology and dementia in Alzheimer's disease.

Previous studies of Alzheimer's disease (AD) have correlated the severity of dementia with either the number of senile plaques or neurofibrillary tangles. We used antibodies raised against amyloid beta/A4 protein of senile plaque cores and tau protein as well as thioflavine S and the Campbell-Switzer modification of the Hicks silver method to examine the hippocampal formation and five neocortical regions from 22 nondemented elderly control subjects and 34 demented patients with cerebral senile plaques and neurofibrillary tangles, without complicating disease processes. Ten control subjects (46%) had no beta/A4 protein deposition. Twelve control subjects (54%) had widespread beta/A4 protein deposition but no neocortical neuritic pathology. Of the 34 patients with AD-type changes, 27 (79%) had widespread senile plaques and neurofibrillary tangles, while 7 (21%) had neocortical senile plaques with few neurofibrillary tangles. All demented patients had widespread beta/A4 protein deposition and neocortical tau-immunoreactive, Hicks silver-positive dystrophic neurites. The neurites were found both free in the neuropil as well as surrounding senile plaques. Quantitative analysis showed that dystrophic neurites were significantly increased in patients with AD compared with control subjects and the number of dystrophic neurites and neurofibrillary tangles correlated with the clinical severity of dementia. Widespread cerebral beta/A4 protein deposition may be necessary but by itself is insufficient for the development of dementia in AD.

Aged↗
PubMed1995

Distribution and expression of the alpha-tubulin mRNA in the hippocampus and the temporal cortex in Alzheimer's disease.

The distribution of the messenger RNA for alpha-tubulin has been investigated by in situ hybridization in the human hippocampus and temporal cortex in normal subjects and in Alzheimer's disease. The alpha-tubulin mRNA was strongly expressed in neurons in the gyrus dentatus, in the Ammon's horn and in cortical layers of the temporal cortex. The same distribution was observed in Alzheimer's disease. An important reduction of the hybridization signal was apparent, however, in areas rich in neurofibrillary lesions, e.g. as in layer II of entorhinal cortex. Neurons containing neurofibrillary tangles exhibited a weaker hybridization signal than adjacent neurons devoid of neurofibrillary tangles. The immunoreactivity for alpha-tubulin was drastically reduced in tangles-bearing neurons. These results indicate that tubulin transcription is reduced in tangles-bearing neurons, a reduction which might play a role in the reported decrease in the number of microtubules in neurons containing neurofibrillary tangles.

Aged↗
PubMed1992

Progressive transformation of the cytoskeleton associated with normal aging and Alzheimer's disease.

Transitional and end-stage forms of neurofibrillary tangles associated with normal aging and Alzheimer's disease were identified using thioflavine staining combined with tau and neurofilament protein immunofluorescence. Normal aging was marked by transitional pathology in layer II of the entorhinal cortex but no neurofibrillary tangles in prefrontal cortex, whereas, in Alzheimer's disease cases, layer II entorhinal neurons had progressed to end-stage neurofibrillary tangles and the prefrontal cortex contained a high representation of transitional forms of the neurofibrillary tangle.

Adolescent↗
PubMed1984

A human ganglioglioma containing paired helical filaments.

Neurofibrillary tangles composed of paired helical filaments were found in a human ganglioglioma. This is the first reported occurrence of neurofibrillary tangles in a neoplasm. These tangles were visible light microscopically with hematoxylin-eosin and Bodian's stains. They were confirmed as neurofibrillary tangles with Congo red staining under polarized light and with thioflavine S fluorescence. Untrastructurally, the tangles were composed of 10-nm filaments twisted in a helix with 80 nm between constructions. Thus, neoplastic proliferation does not preclude production of paired helical filaments. Cells grew from explants of this tumor, but no paired helical filaments were found in the cells examined. Two other gangliogliomas and normal brain tissue studies by the same procedures did not show paired helical filaments. Gangliogliomas that contain neurofibrillary tangles provide an alternative source of abnormal filaments for analysis.

Adolescent↗
PubMed1996

Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine.

It is well known that beta-amyloid accumulates abnormally in Alzheimer's disease; however, beta-amyloid's relationship to cognitive dysfunction has not been clearly established and is often confounded by the presence of neurofibrillary tangles. We used canines to investigate the relationship between beta-amyloid accumulation and cognitive function in an animal model of aging lacking neurofibrillary tangles. The performance of 20 canines (11 purebred beagles and 9 mongrels) on a battery of six cognitive tasks was measured. These tasks included Reward Approach and Object Approach learning, as well as Discrimination, Reversal, Object Recognition, and Spatial learning and memory. Aged canines were impaired on some tasks but not others. beta-Amyloid-immunopositive plaques were found in many of the older animals. Plaques were all of the diffuse subtype and many contained intact neurons detected with double-labeling for neurofilaments. No neurofibrillary tangles were detected. beta-Amyloid was also associated with the processes of many neurons and with blood vessels. Using computerized image analysis, we quantified the area occupied by beta-amyloid in entorhinal cortex, frontal cortex, and cerebellum. Controlling for age-related increases in beta-amyloid, we observed that increased beta-amyloid deposition is strongly associated with deficits on Discrimination learning (r = .80), Reversal learning (r = .65), and Spatial learning (r = .54) but not the other tasks. There were a few differences between breeds which are discussed in the text. Overall, these data suggest that beta-amyloid deposition may be a contributing factor to age-related cognitive dysfunction prior to the onset of neurofibrillary tangle formation.

Alzheimer Disease↗
PubMed1994

Alzheimer's disease with asymmetric atrophy of the cerebral hemispheres: morphometric analysis of four cases.

To examine the clinicopathological correlations in rare Alzheimer's disease patients with asymmetric cerebral atrophy and to compare their pattern of cortical involvement by senile lesions with that observed in other cases with atypical Alzheimer's disease, we performed an extensive neuropathological analysis of the cerebral cortex in four such cases. Three patients presented with severe language impairment but relatively good preservation of praxis and gnosis even after several years of clinical evolution. Cerebral autopsies of these cases revealed a predominant left hemisphere atrophy. Conversely, in one case with marked right hemisphere atrophy, all of the cognitive functions were involved early in the course of dementia. Neurofibrillary tangles and senile plaques were preferentially localized in the prefrontal, temporal and posterior parietal cortex in both hemispheres, whereas the hippocampal formation displayed lower lesion densities than neocortical areas. Significantly higher neurofibrillary tangle and senile plaque densities were found in the more atrophic side in most of the areas studied. The ratio of neurofibrillary tangle and senile plaque densities between the two hemispheres was not correlated with the number of these lesions in the cerebral cortex. These results indicate that the degenerative process in demented cases with interhemispheric asymmetric cerebral atrophy is characterized by a widespread involvement of the neocortex by senile lesions and lacks clear regional topography of neurofibrillary tangle and senile plaque distribution. Moreover, the relative sparing of the hippocampus, comparable to that found in cases with focal progressive dementia, suggests that the dementing process may involve different cortical structures in cases with asymmetric cerebral atrophy than in typical Alzheimer's disease cases.

Aged↗
PubMed2006

Topographic study of Alzheimer's neurofibrillary changes: a personal perspective.

Argentophilic neurofibrillary tangles were described in the cerebral cortex of Alzheimer's disease and later in the pigmented neurons in the brain stem of postencephalitic parkinsonism. In 1961, wide distribution of Alzheimer's neurofibrillary tangles in the central nervous system was observed in endemic fatal neurodegenerative diseases affecting the native Chamorro population on Guam: amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam. Abundant neurofibrillary tangles were found but no senile plaques. A topographic analysis of tangles in cases in Guam and at Montefiore were published in 1962. Thereafter, Alzheimer's neurofibrillary changes were documented in various areas of the nervous system of many other diseases. This communication is a brief review of the topographic investigation of Alzheimer's neurofibrillary changes. Occurrence of tangles in various conditions seems to indicate that various pathological agents can induce tangles. On the other hand, Alzheimer's neurofibrillary tangles, in general, show a rather striking predilection to affect particular neurons in the involved regions.

Alzheimer Disease↗
PubMed1987

The comparative immunoreactivities of brain amyloids in Alzheimer's disease and scrapie.

An antibody was raised to a synthetic peptide corresponding to a published sequence for the first 24 residues of a cerebrovascular amyloid peptide (CVAP). Immunohistochemical staining of tissue sections revealed that the antibody bound extensively to cerebrovascular amyloid in Alzheimer disease (AD/SDAT) and Down's syndrome cases. The antibody bound less extensively to neuritic plaques (primitive and mature) and indetectably to neurofibrillary tangles. The antibody did not label scrapie plaques, scrapie-associated fibrils, or Gerstmann-Sträussler syndrome plaques. Immunoblotting experiments showed that the cerebrovascular amyloid peptide epitopes contaminating the neurofibrillary tangle preparations could be extracted with urea, leaving the neurofibrillary tangles intact. These data confirm that the cerebrovascular amyloid peptide is a component of cerebrovascular amyloid, and suggest that its epitopes are also components of neuritic plaque amyloid. The reduced level of immunostaining on amyloid cores in tissue sections suggests that either the cerebrovascular amyloid peptide epitopes are a minor component of amyloid cores, or that their mode of packing or state of processing in amyloid cores renders them relatively inaccessible to the antibody. We also conclude that the cerebrovascular amyloid peptide is not a component of neurofibrillary tangles. The synthetic cerebrovascular amyloid peptide possesses amyloid-like properties: at neutral pH it forms insoluble aggregates consisting of 5-7-nm fibrils, which form red-green birefringent adducts with Congo red and fluoresce with thioflavine S.

Alzheimer Disease↗
PubMed2004

The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia.

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.

Animals↗
PubMed1996

Evidence of neuronal oxidative damage in Alzheimer's disease.

Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.

Adolescent↗