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W C Benzing

Publications and source records attributed to W C Benzing.

17 recordsLinked to original sources
PubMed1998

The complement cascade in Alzheimer's disease.

Numerous studies show that activated glial cells release increased amounts of several molecules that might contribute to the pathology of Alzheimer's disease (AD), including complement proteins. The complement proteins are particularly noteworthy because of their well-documented ability to induce inflammation, destroy foreign cells and, in certain circumstances, inflict damage to host tissue. There appears to be a general consensus that the early components of the classical complement pathway are found associated with senile plaques in AD brain; of some dispute is whether the later complement products are truly found in AD brain. An unequivocal demonstration of the terminal complement activation products in AD brain is important in strengthening the hypothesis that these products contribute to disease pathology. To date, it has been difficult to determine the extent to which complement activation contributes to the neuropathology of AD. Given the potential detrimental consequences of complement activation in AD brain, there is compelling reason to identify potential therapeutic agents that might attenuate complement activity in this disease. Based on the evidence that Abeta is a likely activator of complement in AD, and on the understanding of the nature of Abeta-C1q binding, it is possible that drugs might be developed that will slow complement activity in the AD brain without compromising this defense mechanism throughout the rest of the body.

Journal Article↗
PubMed1995

Increased number of NADPH-d-positive neurons within the substantia innominata in Alzheimer's disease.

NADPH-diaphorase histochemistry labels neurons containing nitric oxide synthase, the synthesizing for nitric oxide within the central nervous system. Quantitation revealed a statistically significant increase in the density of intensely (type 1) and moderately (type 2) but not lightly (type 3) NADPH-diaphorase stained neurons within the substantia innominata in AD as compared with age-matched controls. Increased numbers of NADPH-diaphorase neurons suggest excess nitric oxide production which may be neurotoxic to surrounding cholinergic neurons within the substantia innominata in Alzheimer's disease.

Aged↗
PubMed1995

Apolipoprotein E immunoreactivity within neurofibrillary tangles: relationship to Tau and PHF in Alzheimer's disease.

The present immunohistochemical study determined the relationship between ApoE and the expression of the cytoskeletal protein tau (Tau2) and paired helical filaments (PHF), within the magnocellular neurons of the nucleus basalis of Meynert and layer II stellate neurons of the entorhinal cortex in Alzheimer's disease (AD). Although nearly all ApoE immunoreactive perikarya within these two brain regions were PHF immunoreactive, not all PHF and Tau2 containing neurons stained for ApoE in AD. Moreover, more Tau2-immunostained neurons, as compared to PHF, were ApoE immunonegative. This was particularly evident in a population of control subjects which exhibited AD-like pathology intermediate between the AD and normal aged individuals. Thus, neurons within the nucleus basalis of Meynert and entorhinal cortex layer II stellate exhibit evidence of cytoskeletal pathology prior to displaying ApoE. These observations suggest that (1) ApoE plays a secondary role in NFT formation or (2) this protein is accumulated within these neurons in response to reparative process(es) induced by NFT-associated neuronal damage.

Aged↗
PubMed1993

Immunocytochemical distribution of peptidergic and cholinergic fibers in the human amygdala: their depletion in Alzheimer's disease and morphologic alteration in non-demented elderly with numerous senile plaques.

As part of an ongoing investigation devoted to understanding the pathogenesis of senile plaques, we employed histochemical and immunocytochemical techniques to examine the distribution and cytologic features of acetylcholinesterase (AChE), choline acetyltransferase (ChAT), somatostatin (SOM), neurotensin (NT) and substance P (SP) containing fibers and neurons within the amygdala of: (1) patients with Alzheimer's disease (AD); (2) age-matched non-demented controls (NC); and (3) a group of non-demented cases, who upon postmortem neuropathologic examination exhibited sufficient numbers of senile plaques to be classified as AD. This latter group was referred to as high plaque non-demented (HPND). For every case, the distribution of immunolabeled fibers and neurons were determined for each transmitter throughout the various subnuclei of the amygdala. In addition, in the AD and HPND cases the topographic distribution of senile plaques was determined throughout the amygdala using thioflavine-S and Bielschowsky silver methods. In the amygdala, the distribution and density of senile plaques were not bound by conventional cytoarchitectural groupings but rather were most dense in the ventromedial regions of the amygdala with decreasing density in dorsal and lateral directions. Importantly, the density and distribution of senile plaques failed to correlate with the normal topography and/or density of the various peptidergic or cholinergic fibers within the amygdala. The finding that plaques do not correlate with the topographic distribution of any specific transmitter system suggests that plaques likely do not arise from the degeneration of a single neurotransmitter system (i.e., the cholinergic system). However, the finding that in AD a transmitter is most markedly depleted in regions of greatest plaque density, suggests certain constituents of the plaque (e.g. beta-amyloid) may be contributing to the degeneration of local fibers. The extent to which a transmitter was depleted in AD patients varied considerably among those four investigated with the cholinergic and NT systems displaying the most dramatic reductions, followed by SP and SOM. Despite these differential reductions in fiber density, all four neurotransmitters were found localized within dystrophic neurites and in most instances these dystrophic neurites were associated with thioflavine-positive senile plaques. In contrast to the AD cases, the HPND cases were characterized by no significant reductions in immunolabeled fibers, although immunostained dystrophic neurites were very prevalent in the HPND cases. These data suggest that dystrophic neurites occur very early in the disease process and likely precede the actual loss of fibers when or if it occurs.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Galanin immunoreactivity within the primate basal forebrain: evolutionary change between monkeys and apes.

Galanin immunoreactivity (GAL-ir) is differentially expressed within the basal forebrain of monkeys and humans. Most monkey magnocellular basal forebrain neurons colocalize GAL-ir. In contrast, virtually no human magnocellular basal forebrain neurons express GAL-ir. Rather, an extrinsic galaninergic fiber plexus innervates these neurons in humans. The present study examined the expression of GAL-ir within the basal forebrain of apes to establish the phylogenetic level at which this transformation occurs. The staining patterns of GAL-ir within the basal forebrain of both lesser (gibbons) and great (chimpanzee and gorilla) apes were compared to that previously observed within monkeys and humans. All apes displayed a pattern of basal forebrain GAL-ir indistinguishable from humans. GAL-ir was not expressed within ape basal forebrain magnocellular neurons as seen in monkeys. Rather like humans, a dense collection of GAL-ir fibers was seen in close apposition to magnocellular perikarya. In addition, a few GAL-ir parvicellular neurons were scattered within the ape basal forebrain. These data indicate that the evolutionary change in the expression of GAL-ir within the primate basal forebrain occurs at the branch point of monkeys and apes.

Animals↗
PubMed1993

Evidence that transmitter-containing dystrophic neurites precede those containing paired helical filaments within senile plaques in the entorhinal cortex of nondemented elderly and Alzheimer's disease patients.

Within the amygdala of elderly subjects and patients with Alzheimer's disease (AD), we recently found evidence suggesting amyloid beta-protein (A beta P) deposition occurs before the appearance of dystrophic neurites. Moreover, these data suggested dystrophic neurites initially lack evidence of cytoskeletal pathology although with time and further maturation, the dystrophic neurites display an altered cytoskeleton as evidenced by their immunoreactivity to Alz-50 and paired-helical filaments (PHF). These findings are of particular relevance to our understanding of the sequence of pathologic events in AD and thus it has become important to determine whether these events are unique to the amygdala or are representative of a more general pattern which can be found throughout the brain. Using a battery of antibodies to markers that are characteristic of AD pathology (i.e., A beta P, PHF, and Alz-50), three peptidergic neurotransmitters (neurotensin, somatostatin, and substance P), and one neurotransmitter biosynthetic enzyme (choline acetyltransferase), we examined the entorhinal cortex (EC) of three groups of subjects (AD, normal elderly, and a group of nondemented elderly with numerous senile plaques). The EC was studied, in part, because it is well recognized as a brain region displaying severe and, most importantly, early pathologic changes. Like the amygdala, we found evidence that amyloid beta-protein immunoreactive (A beta P-IR) and thioflavine-S-positive senile plaques occur within the EC prior to the appearance of transmitter-, Alz-50-, or PHF-immunoreactive dystrophic neurites. We also observed transmitter-immunoreactive dystrophic neurites in the absence of Alz-50 or PHF-immunolabeled dystrophic neurites and transmitter- and Alz-50-IR dystrophic neurites in the absence of those containing PHF. Collectively, these findings were similar to those seen within the amygdala and thus reinforced the concept that A beta P deposition is the primary event in plaque pathology, and this deposition is subsequently followed by the appearance of dystrophic neurites which retain their transmitter phenotype yet lack an altered cytoskeleton. With time, these dystrophic neurites develop cytoskeletal alterations and become immunoreactive to Alz-50 and PHF.

Adult↗
PubMed1993

Evidence that transmitter-containing dystrophic neurites precede paired helical filament and Alz-50 formation within senile plaques in the amygdala of nondemented elderly and patients with Alzheimer's disease.

Immunocytochemical techniques were employed to examine the temporal ordering whereby amyloid beta-protein (A beta P) and neuronal elements collectively come together to form senile plaques in Alzheimer's disease (AD). Specifically, we addressed three questions: (1) whether A beta P deposition precedes or follows neuritic changes; (2) whether paired helical filament (PHF) formation is an early or late event in the genesis of the dystrophic neurites which participate in plaque formation; and (3) whether the density of senile plaques displays any relationship with the prevalence of PHF or Alz-50 containing neurons. To address these questions we studied the amygdala from a group of patients with AD, a group of nondemented age-matched individuals exhibiting a sufficient number of senile plaques to be classified by neuropathological criteria as AD, and a group of age-matched controls without AD pathology. Amyloid-bearing plaques were demonstrated by A beta P immunolabeling and thioflavine-S staining. Neuritic changes in the form of dystrophic neurites were observed with the aid of antibodies against PHF, Alz-50, as well as antibodies against several neuropeptides (i.e., substance P, somatostatin, and neurotensin) and the acetylcholine biosynthetic enzyme, choline acetyltransferase. By using a graded range of pathologic changes both within and across the patient population to provide us with a means of evaluating plaque deposition from its earliest to most advanced stages of development, we observed in patients and/or regions of the amygdala displaying a mild degree of pathologic change A beta P deposition in the absence of any neuritic changes. With increasing density of A beta P, however, we began to observe dystrophic neurites within plaques. In regions of relatively few plaques, the dystrophic neurites were immunolabeled only with antibodies against the various neurotransmitters and they lacked evidence of cytoskeletal pathology (i.e., Alz-50 or PHF). Only as the density of A beta P increased further within a region, were dystrophic neurites observed that exhibited Alz-50 or PHF. In no instance did we observe a relationship between the density of A beta P deposition and the density of Alz-50 or PHF-immunoreactive neurons. Collectively, our data suggest that the deposition of A beta P is an early pathologic event in senile plaque formation. Thereafter, swollen neurites can be seen in the vicinity of A beta P. This early neuritic response, which can first be visualized by immunolabeling for one or another transmitter substance, is followed by alterations in the cytoskeleton as recognized initially by antibodies to Alz-50 and subsequently by the presence of PHF.

Adult↗
PubMed1993

Alzheimer's disease-like dystrophic neurites characteristically associated with senile plaques are not found within other neurodegenerative diseases unless amyloid beta-protein deposition is present.

Swollen, bulbous-shaped (dystrophic) neurites are a common pathologic feature of Alzheimer's disease (AD) and represent one of the most abundant neuritic abnormalities within the brains of patients with this disease. In the present study, we sought to determine whether the dystrophic neurites which are observed in association with senile plaques are unique to AD or whether they are characteristic of a more generalized process of neuritic and/or neuronal degeneration which can be observed in other neurodegenerative diseases. To accomplish this, we examined post-mortem brain material from patients with AD, Parkinson's disease (PD), Parkinson's disease with associated AD, Parkinson's disease with dementia yet without AD pathology, Huntington's disease (HD), Pick's disease and normal age-matched controls (NC). Using a battery of antibodies to amyloid beta-protein (A beta P), paired-helical filaments (PHF), tyrosine hydroxylase, substance P, neurotensin, and somatostatin we found that immunolabeled dystrophic neurites of the type characteristically observed in AD, were seen only in cases and in brain regions where A beta P deposition was present. More specifically, brain areas known to display severe afferent and/or local degenerative changes such as the caudate and putamen in all three PD groups, the caudate in the HD cases, and the temporal cortex in the HD and Pick's cases were conspicuously free of these swollen neurites unless A beta P deposition was also present.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Distribution of neurotensin immunoreactivity within the human amygdaloid complex: a comparison with acetylcholinesterase- and Nissl-stained tissue sections.

In a previous study, we reported marked depletion of neurotensin-immunoreactivity (NT-IR) within selected regions of the amygdala of patients with Alzheimer's disease. The significance of these observations was partly obscured largely because we lacked a thorough understanding of the innervation pattern of neurotensin in the normal human amygdala. Accordingly, in the present study, we used a polyclonal antibody against neurotensin to characterize the distribution and morphology of neurotensin-immunoreactive neuronal elements within the human amygdaloid complex. NT-IR occurred in a topographic manner that respected the cytoarchitectural boundaries of the amygdaloid subregions as defined by Nissl staining and acetylcholinesterase histochemistry. Most NT-IR in the amygdala was contained within beaded fibers and dot-like puncta. Within the subnuclei of the amygdala, immunoreactive neuritic elements were most dense within the central nucleus followed by the medial nucleus and intercalated nuclei. The anterior amygdaloid area, basal complex, paralaminar nucleus, cortical nucleus, cortical-amygdaloid transition area, and amygdalohippocampal area contained moderate densities of immunoreactivity. The accessory basal and lateral nuclei exhibited scant NT-IR. Immunoreactive neurons were found only within the anterior amygdaloid area and the central, medial, intercalated, and lateral capsular nuclei. The distribution of NT-immunoreactive processes and cell bodies within selected regions of the amygdala provides an anatomical substrate that may explain, in part, the neuromodulatory actions of neurotensin upon autonomic, endocrine, and memory systems.

Acetylcholinesterase↗
PubMed1991

Striatal glutamic acid decarboxylase immunoreactivity is increased after dopaminergic deafferentation: densitometric analysis.

Several lines of evidence suggest that dopamine exerts a chronic inhibitory action on GABAergic cells in the striatum, and striatal glutamic acid decarboxylase (GAD) mRNA levels are increased after ipsilateral dopaminergic denervation. In the present study we have used GAD immunocytochemistry to assess whether dopaminergic denervation results in an increase in GAD protein synthesis. In three 6-hydroxydopamine-lesioned animals, there was a perceptible increase in the density of GAD-immunoreactive (ir)staining on the side ipsilateral to the lesion. Computer-assisted densitometric analysis showed a significant increase in GAD-ir staining in the ipsilateral striatum compared to the contralateral (control) side. These data suggest that removal of striatal dopaminergic innervation results in an increase in the amount of immunoreactive GAD, the rate limiting enzyme in the synthesis of GABA.

Afferent Pathways↗
PubMed1990

Reduction of neurotensin immunoreactivity in the amygdala in Alzheimer's disease.

The density of neurotensin immunoreactivity (NT-IR) was dramatically decreased in 6 of 12 amygdaloid nuclear subregions in patients with Alzheimer's disease (AD) compared to age-matched normals. Diminution of NT-IR was most pronounced in amygdaloid regions containing the greatest number of senile plaques. This contrasts to our previous findings of little, if any, loss of substance P or somatostatin immunoreactivity within these same regions. The present findings corroborate biochemical reports of a decrease in NT-IR in the AD amygdala and suggest that this peptide may be selectively affected relative to other neuropeptides.

Aged↗
PubMed1989

Substance P and somatostatin coexist within neuritic plaques: implications for the pathogenesis of Alzheimer's disease.

In recent years the present authors and others have sought to determine the neurochemical composition of the dilated neuronal processes found within neuritic plaques of patients with Alzheimer's disease. To date a number of neurotransmitter and neuropeptide systems have been observed within different plaques, yet at present it is unclear whether individual human plaques contain more than one transmitter substance. In the present study a highly sensitive dual-immunolabeling procedure was employed and it was demonstrated that substance P and somatostatin-immunoreactive profiles coexist within single senile plaques of patients with Alzheimer's disease. Coexistence of somatostatin and substance P immunoreactivity within plaques was observed in the hippocampus and amygdala but not in the neocortex, although the latter region contained plaques within which somatostatin and substance P existed alone. The frequency with which we observed one or more neuropeptide within plaques was relatively low and in fact most plaques contained neither substance P nor somatostatin immunoreactivity. In addition, a large number of swollen peptidergic processes were observed outside of plaques. The significance of these observations with respect to the pathogenesis of Alzheimer's disease is discussed.

Aged↗
PubMed1989

Preserved learning and memory in amnesia: intact adaptation-level effects and learning of stereoscopic depth.

Amnesic patients and control Ss performed similarly on 2 memory tests. In Experiments 1A and 1B, amnesic patients exhibited intact adaptation-level effects: An experience lifting and judging a group of weights influenced their judgments of a 2nd group of weights 20-25 min later. The effect did not depend on peripheral accommodation, because Ss used 1 hand during their 1st encounter with the weights and the opposite hand during their 2nd encounter. In Experiment 2, amnesic patients acquired at a normal rate the ability to perceive binocular depth using random-dot stereograms. In both experiments, amnesic patients benefited from recent experience, despite the fact that they could not remember their prior experience accurately. The preserved memory abilities demonstrated here appear to be examples of implicit, or nondeclarative, memory.

Adaptation, Psychological↗
PubMedDate not supplied

Apolipoprotein E-immunoreactivity in aged rhesus monkey cortex: colocalization with amyloid plaques.

In the present study, we examined the relationship between ApoE and amyloid containing profiles within the cerebral cortex of young, middle aged, and aged Rhesus monkeys. Polymerase chain reaction analysis revealed a pattern consistent with the ApoE e4 phenotype in the rhesus monkey similar to that reported in humans. We found numerous ApoE immunoreactive plaques within the temporal neocortex and amygdala, whereas the hippocampus contained only a few such plaques. Although virtually all ApoE-immunoreactive plaques coexpressed beta-amyloid, most plaques were beta A4 positive/ApoE immunonegative within the aged monkey cortex. Moreover, we observed a close correspondence between ApoE and thioflavin-positive (i.e., amyloid) plaques suggesting that ApoE may play a critical role in the conversion of beta A4 to its beta-pleated form. Because ApoE, beta A4 and amyloid are expressed in plaques within the aged Rhesus macaque cortex, this species may provide an in vivo model for investigations aimed at clarifying the interactions between these proteins in normal and pathologic aging.

Aging↗
PubMedDate not supplied

Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice.

Chronic expression of inflammatory cytokines, including interleukin-1beta, tumor necrosis factor alpha, and interleukin-6, by glia may underlie the neurodegenerative events that occur within the brains of patients with Alzheimer's disease (AD). The present study determined whether these markers of inflammation could be observed within the brains of Tg(HuAPP695.K670N/M671L)2576 transgenic mice (Tg2576) that have recently been shown to mimic many features of AD. Interleukin-1beta- and tumor necrosis factor alpha-immunopositive microglia were localized with thioflavine-positive (fibrillar) Abeta deposits. Moreover, interleukin-6 immunoreactive astrocytes surrounded fibrillar Abeta deposits. These findings provide evidence that Tg2576 mice exhibit features of the inflammatory pathology seen in AD and suggest that these mice are a useful animal model for studying the role inflammation may play in this disease.

Aging↗