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D M Armstrong

Publications and source records attributed to D M Armstrong.

At least 37 records · Page 2Linked to original sources
PubMed1997

The loss of GluR2(3) immunoreactivity precedes neurofibrillary tangle formation in the entorhinal cortex and hippocampus of Alzheimer brains.

Double-immunolabeling techniques were employed to examine the distribution of GluR2(3) subunits and markers of early cytoskeletal changes (mab MC1) within the entorhinal cortex (EC) and hippocampus of cases with varying degrees of Alzheimer disease (AD) pathology (stages I-VI by Braak and Braak). In addition near-adjacent tissue sections were double-immunolabeled using antibodies against GluR2(3) and a marker of normal neuronal cytoskeleton (MAP2). In those cases classified as stages I-II, most layer II neurons of the EC and pyramidal neurons in the CA1/subiculum were double-labeled with GluR2(3) and MAP2. An occasional MC1-labeled cell was observed, yet in no instance were these neurons double-labeled with GluR2(3). In cases with moderate AD pathology (stages III-IV), layer II of the EC and CA1/subiculum were characterized by a substantial loss of GluR2(3)-labeled neurons, while many were still immunoreactive to MAP2. Notably, the loss of GluR2(3) immunolabeling was accompanied by an increasing number of MC1-positive neurons. In no instance were GluR2(3) and MC1 co-localized within the same neuron. In cases with severe AD pathology (stages V-VI), the EC and CA1/subiculum were almost completely devoid of GluR2(3)-positive neurons. MAP2-labeled neurons also were reduced in number. In contrast, both regions contained an abundance of MC1-positive cells. That GluR2(3) and MC1 are not observed in the same neuron, together with the observation that the number of GluR2(3)-labeled neurons decreases as the number of MC1-positive cells increases, suggest that a loss of GluR2(3) immunolabeling precedes the appearance of MC1 immunolabeling.

Aged↗
PubMed1996

Distribution of AMPA receptor subunits in the nucleus basalis of Meynert in aged humans: implications for selective neuronal degeneration.

Immunocytochemical techniques using polyclonal antibodies directed against GluR1 and GluR2/3 subunits of the AMPA-selective receptor complex were used to examine the distribution of these receptor subunits within the nucleus basalis of Meynert (NBM) of non-demented elderly humans. Both somata and processes of magnocellular neurons within the NBM were intensely immunoreactive to GluR1 antibodies. In contrast, within the same region GluR2/3 immunolabeling was largely absent, although GluR2/3-positive neurons were abundantly distributed within adjacent brain regions (i.e., amygdala, entorhinal cortex and hippocampus). These data suggest that NBM neurons may be unique compared to those of other brain regions, in their response to glutamatergic excitation as mediated via non-NMDA receptors and be particularly vulnerable to glutamate excitotoxicity via a mechanism involving the destabilization of intracellular calcium.

Aged↗
PubMed1996

Role of the cerebellum and motor cortex in the regulation of visually controlled locomotion.

An account is given of the current state of knowledge of the contributions of the cerebellum and the forelimb motor cortex (MC) to the neural control of walking movements in the cat. The main emphasis is on information obtained by recording from single MC and cerebellar neurones in chronically instrumented cats engaged in walking on the rungs of a horizontal ladder, a form of locomotion that is heavily dependent on visual input and for which the integrity of MC is essential. Evidence from the authors' laboratory and from other studies is presented which establishes that MC neurones, including pyramidal tract neurones, show higher levels of activity during ladder walking than during overground walking (i.e., when less constraint exists over the locus of footfall) and that this increase is greatest in late swing-early stance in the contralateral forelimb, consistent with one role of MC being to help determine the locus of footfall. However, many MC neurones develop peak activity at other times in the step cycle, and a comparison with recordings during treadmill walking suggests MC may also help regulate stance duration when walking speed is an important performance variable. Recordings from Purkinje cells and cerebellar nuclear neurones show that during ladder walking step-related activity is widespread in the vermal, paravermal, and crural regions of cortex and in the interposed and dentate nuclei. Nuclear cell activity is so timed that it could be contributing to producing the locomotor rhythms evident in MC cells, although this is not yet proven. Results are also presented and discussed relating to MC and cerebellar neuronal responses that occur when a step onto an unstable rung results in an unexpected external perturbation of the forelimb step cycle. MC responses begin with onset latency as short as 20 ms so that MC may assist spinal reflex mechanisms to produce a post hoc compensatory change in motor output. However, work in progress suggests that corresponding responses in paravermal cerebellum are weak and infrequent, so provisionally it seems that the MC responses are initiated via pathways that do not pass through the cerebellum. By contrast, current work involving a paradigm in which a ladder rung is motor driven to a new position as the animal approaches (thereby providing a visual cue that an adaptive change in gait will soon be required) is revealing in lateral cerebellar neurones, including dentate neurones, changes in discharge that are time locked to the execution of an adapted pace. In addition, there are prominent earlier responses, which begin at short latency after the onset of rung movement. These apparently visual responses have characteristics that encourage the speculation that they may represent a cerebellar signal that "primes for action" other more directly motor regions of the central nervous system.

Animals↗
PubMed1995

AMPA-selective glutamate receptor subtype immunoreactivity in the aged human hippocampal formation.

It has been hypothesized that, in Alzheimer's disease, glutamate-mediated excitotoxicity contributes to the degeneration of selected populations of neurons. In the present study, immunocytochemical techniques were used to determine the distribution and anatomical features of GluR1- and GluR2/3-immunolabeled cell bodies and processes within the hippocampal formation of normal (i.e., no pathology) elderly humans. The results of this study provide an essential baseline with which to compare the expression and distribution of glutamate receptor subunits within the brains of patients with Alzheimer's disease. With respect to GluR1 immunoreactivity, the molecular layer of the dentate gyrus displays the most intense immunolabeling of any hippocampal structure. Contributing to this intense labeling are apical dendrites that arise from neurons within the adjacent granule cell layer. Interestingly, GluR1-labeled neurons account for a relatively small percentage of the total number of neurons as revealed by Nissl staining in the granule cell layer. In contrast, GluR2/3-labeled neurons are densely distributed throughout the granule cell layer, yet they provide relatively few processes to the adjacent molecular layer compared to GluR1-positive processes. GluR1 labeling is also prominent within the CA fields of Ammon's horn, with CA2 > CA3 > CA1 > or = CA4. Most prominent within the CA fields are the labeled dendrites of pyramidal neurons. In many instances, apical dendrites can be traced into the adjacent stratum radiatum, where they impart a deep striated appearance to this region of the hippocampus. Robust GluR2/3 labeling is also observed within the pyramidal layer of Ammon's horn, with an order of staining intensity similar to that observed for GluR1. However, unlike GluR1 labeling, which is localized predominantly along dendrites, GluR2/3 labeling is observed primarily in association with cell bodies. Collectively, these data suggest that the molecular composition of the AMPA receptor complex may differ between the dendrite and soma of granule and pyramidal neurons within the hippocampal formation, so functionally we may predict that these two regions of the neuron would respond differently following glutamate receptor stimulation.

Aged↗
PubMed1995

Reduction of AMPA-selective glutamate receptor subunits in the entorhinal cortex of patients with Alzheimer's disease pathology: a biochemical study.

Using biochemical techniques we determined concentrations of the AMPA-selective glutamate receptor subunits GluR1 and GluR2/3 in the entorhinal cortex of patients with Alzheimer's disease pathology and age-matched controls. Tangle density was also determined in anatomically matched samples and correlated with GluR1 and GluR2/3 receptor concentration. In Alzheimer's disease brain, Western blot analysis revealed average reductions of 43% and 38% for GluR1 and GluR2/3, respectively. Based on previous immunohistochemical studies, we infer that the majority of protein reduction was due to decreases in GluR1 and GluR2/3 immunolabeled elements in the more superficial layers of the entorhinal cortex (layers II and III). These layers of the entorhinal cortex contained numerous neurofibrillary tangles in Alzheimer's disease, but neither GluR1 nor GluR2/3 protein concentration correlated significantly with tangle density. We hypothesize that the decrease in specific glutamate receptor subunits, particularly GluR2/3, may contribute to the vulnerability of neurons in the entorhinal cortex via mechanisms involving calcium conductance through AMPA-selective channels.

Aged↗
PubMed1995

Step phase-related excitability changes in spino-olivocerebellar paths to the c1 and c3 zones in cat cerebellum.

1. Chronically implanted microwires were used to record extracellular field potentials generated in the c1 and c3 zones in the cortex of lobules V and VI of the cerebellum by non-noxious stimuli delivered to the superficial radial nerve in the ipsilateral forelimb. Responses due to input via climbing fibre afferents were studied; their latency and other characteristics identified them as mediated mainly via the dorsal funiculus spino-olivocerebellar path (DF-SOCP). 2. Responses at individual sites were studied repeatedly with a range of stimulus intensities and during two different behaviours: quiet rest and steady walking on an exercise belt. For responses during walking, step histograms were constructed showing response mean size during different tenths of the step cycle in the ipsilateral forelimb, both in absolute terms and relative to mean size during rest. 3. Step histograms for the same site on different days or different stimulus intensities varied appreciably in form but in both cases the timing of the largest response was usually the same or shifted by only one step tenth. 4. In both zones the largest responses during walking occurred overwhelmingly during the E1 step phase when the limb is extended forwards and down to establish footfall. Least responses were much less uniform in timing but were mostly during stance, particularly its early (E2) part. 5. In many histograms the smallest responses were smaller in mean size than the responses during rest while the largest were larger. These changes were not paralleled by changes in nerve volley size, so presumably reflect step-related central changes in pathway excitability. Facilitations and depressions were differently affected by stimulus intensity and sometimes occurred independently, suggesting generation by separate mechanisms. 6. In both zones there were differences between recording sites which suggests that different DF-SOCP subcomponents innervate different parts of the zones. However, no systematic differences could be firmly established between the medial and lateral subzones of the c1 zone. 7. The results are discussed in relation to the hypothesis that the DF-SOCP constitutes the afferent limb of a transcerebellar mechanism involved in adapting the evolving step.

Animals↗
PubMed1995

AMPA-selective glutamate receptor subtype immunoreactivity in the hippocampal formation of patients with Alzheimer's disease.

Immunocytochemical techniques were employed in order to examine the distribution and relative intensity of the AMPA receptor subunits GluR1 and GluR2/3 within the hippocampal formation of normal controls and Alzheimer's disease (AD) cases. Throughout our investigation we examined cases exhibiting a wide range of pathologic severity, thus allowing us to correlate our immunohistochemical data with the extent of pathology. Specifically, we investigated the distribution of these receptor subunits in hippocampal sectors that are particularly vulnerable to AD pathology (i.e., CA1 and subiculum) and compared these findings with those obtained following examination of sectors that are generally resistant to pathologic change (i.e., CA2/3, dentate gyrus). Within vulnerable sectors we observed a variable loss of GluR1 and GluR2/3 immunolabeling. The degree to which these proteins were reduced appeared to correlate with the extent of neurofibrillary pathology and cell loss. Despite the loss of labeled cells, the intensity of immunolabeling within the remaining neurons was comparable with, and in many instances even greater than, that observed in control cases. Within resistant sectors, the distribution of immunoreactive elements was comparable in both case groups yet the intensity of immunolabeling was markedly increased in AD cases, particularly in the molecular layer of the dentate gyrus and in the stratum lucidum of CA3 (i.e., the termination zones of perforant pathway and mossy fibers). In addition, within AD cases dramatic increases were observed within the supragranular and polymorphic layer of the dentate gyrus (i.e., the terminal zones of sprouting mossy fiber collaterals). The increase in GluR1 and GluR2/3 immunolabeling is hypothesized to occur in response to the deafferentation of selected glutamatergic pathways. Moreover, our data support that hippocampal plasticity is preserved, even in severe AD cases, and suggest a critical role for AMPA receptor subunits in this plasticity and in maintaining hippocampal functioning.

Aged↗
PubMed1995

Functional evidence for the presence of nitric oxide synthase in the dorsal motor nucleus of the vagus.

BACKGROUND & AIMS: Histochemical studies indicate that reduced nicotinamide adenine dinucleotide phosphate diaphorase, the nitric oxide synthase-related enzyme, is present in the dorsal motor nucleus of the vagus of the cat. We have previously shown in vitro that NO synthase is present in this nucleus in the rat and that the excitatory effect of N-methyl-D-aspartate on these neurons is in part caused by NO formation. The aim of this study was to obtain functional evidence for the presence of NO synthase in the cat dorsal motor nucleus of the vagus. METHODS: L-Glutamate, L-arginine, D-arginine, the NO donor S-nitroso-N-acetyl-penicillamine, and the NO synthase inhibitor NG-nitro-L-arginine-methyl ester were unilaterally microinjected into the rostral dorsal motor nucleus of anesthetized cats, and antral and pyloric motility were monitored using extraluminal force transducers. RESULTS: Microinjection of L-arginine increased gastric motility, whereas D-arginine had no effect. Vagotomy eliminated the L-arginine-induced increases. Microinjection of S-nitroso-N-acetyl-penicillamine increased antral motility. NG-Nitro-L-arginine-methyl ester prevented L-arginine from exerting an effect on gastric motility. CONCLUSIONS: Motility increases obtained after microinjection of L-arginine into the dorsal motor nucleus and prevention of these motility increases with microinjection of a NO synthase inhibitor provide functional evidence for the presence of NO synthase in the dorsal motor nucleus of the vagus in the cat.

Animals↗
PubMed1995

Atomic force microscopy of paired helical filaments isolated from the autopsied brains of patients with Alzheimer's disease and immunolabeled against microtubule-associated protein tau.

Atomic force microscopy was employed to study the structural features of paired helical filaments isolated from autopsied brains of Alzheimer's disease patients. The identity of paired helical filaments was confirmed following a specific immunogold labeling using antibodies directed against the microtubule-associated protein tau, which is the main constituent of paired helical filaments. Computer-assisted analysis of high resolution, three-dimensional images allowed us to study the longitudinal and cross-sectional profiles of individual filaments. Vertical dimensions of filaments were assessed along these sectional profiles. The smallest vertical diameter (6.66 +/- 0.78 nm) was obtained at the level of the greatest lateral profile (ie, "loop"), while the greatest vertical diameter was two times larger (13.68 +/- 1.46 nm) and was obtained at the level of the smallest lateral profile (ie, "crossover") of the filament. Based on the shapes of these sectional profiles and their vertical dimensions, paired helical filaments appeared to be composed of two identical integral subunits, each of a circular cross-sectional profile of approximately 7 nm in diameter, wound around one another in a left helical manner, with a 7-nm center-to-center separation. Half-period of this helix was estimated at 81.4 +/- 2.1 nm. Serial cross-sectional profiles of paired helical filaments were further utilized to construct a theoretical model of their internal organization. This model suggests that each structural subunit of the paired helical filament incorporates at least four identical protofilaments.

Alzheimer Disease↗
PubMed1994

Photochemical brain injury in rats triggers DNA fragmentation, p53 and HSP72.

The aim of the study was to examine whether apoptosis, apoptosis-related protein p53 and heat-shock protein (HSP) 72 participate in the response of the brain to focal injury. Male Sprague-Dawley rats received intravenously a photosensitive dye rose bengal. Unilateral cortical thrombosis was induced by illuminating the skull of rose bengal-treated rats for 10 min with a focused beam of light. Animals were killed and brains were processed for immunohistochemical detection of DNA fragmentation, p53, and HSP72 kD. DNA fragmentation and p53 were increased only in the perifocal area in the cortex ipsilateral to the thrombotic focus, while HSP72 increased throughout the ipsilateral cortex, except in the immediate perifocal area. The results suggest that in response to focal brain injury, some cells die through an apoptotic process that might involve an accumulation of p53.

Animals↗
PubMed1994

LIGA20, a lyso derivative of ganglioside GM1, given orally after cortical thrombosis reduces infarct size and associated cognition deficit.

A bilateral photochemically induced thrombotic lesion of rat sensorimotor cortex (approximately 3 mm in diameter and 25 mm3 in volume) is associated with a persistent cognition (learning and memory) deficit, which was evaluated with water maze tasks. The N-dichloroacetylsphingosine derivative of lysoGM1 (LIGA20) administered after the lesion either i.v. or per or reduces the infarct size by 30-40% and attenuates the associated cognition deficits, presumably by limiting the extent of damage of neurons at risk located in the surroundings of the infarcted core (i.e., area penumbra). The LIGA20 protection is dose and time dependent. Maximal protection is afforded by a single dose of LIGA20 of 34 mumol/kg i.v. 1 hr after lesion or by a dose of 270 mumol/kg per os when administered 1 hr and 24 hr after the lesion. The protective effect of LIGA20 can be observed when the drug is administered i.v. up to 6 hr after the lesion. The protective efficacy of the oral administration of LIGA20 is related to its physiochemical properties, which, unlike those of GM1, allow absorption from the gastrointestinal tract. LIGA20 given orally reaches the brain promptly and rapidly inserts into the neuronal membranes. Here, by an unknown molecular mechanism, LIGA20 selectively reduces the pathological amplification of Ca2+ signaling elicited by persistent stimulation of ionotropic glutamate receptors in the area penumbra.

Administration, Oral↗
PubMed1994

AMPA-selective glutamate receptor subtype immunoreactivity in the entorhinal cortex of non-demented elderly and patients with Alzheimer's disease.

The present work employed immunocytochemical techniques and examined the distribution and cytological features of the AMPA receptor subunits, GluR2/3 and GluR1 within the entorhinal cortex of non-demented elderly (NC), patients with neuropathological and clinical verification of Alzheimer's disease (AD) and patients without a clinical history of dementia yet exhibiting sufficient quantities of senile plaques to meet neuropathological criteria of Alzheimer's disease (HPND). In NC cases, GluR2/3-immunolabeled neurons were abundantly distributed throughout layers II, III, V and VI of the entorhinal cortex. In contrast, GluR1-positive cells were comparatively sparse in number and largely restricted to layers V and VI. In AD, GluR2/3- and GluR1-labeled neurons were markedly reduced. Similarly, adjacent Nissl-stained tissue sections revealed substantial cell loss in the entorhinal cortex thus providing a reasonable explanation for the loss of these receptor subunits. Importantly, a dramatic loss of GluR2/3- and GluR1-immunolabeled neurons is also observed in the HPND cases, although examination of Nissl-stained tissue sections reveals little if any evidence of cell loss. The latter data suggest that a 'down-regulation' of these receptor subunits occurs prior to the actual loss of these cells. Furthermore, we hypothesize that the decrease of specific AMPA receptor subunits may influence neuronal vulnerability via a mechanism involving increased intracellular calcium and the destabilization of intracellular calcium homeostasis.

Aged↗
PubMed1994

The distribution of cholinergic perikarya with respect to enkephalin-rich patches in the caudate nucleus of the adult cat.

The distribution of cholinergic interneurons with respect to enkephalin-rich patches in the caudate nucleus of the cat was examined using both computer-assisted 3-D reconstruction and immunocytochemical techniques. Examination of the 3-D distribution of perikarya staining for choline acetyltransferase (ChAT) revealed that these cells were not evenly distributed within the caudate nucleus but exhibited areas of increased and decreased density. Comparison of the 3-D distribution of cholinergic perikarya to that of the enkephalin-rich patches indicated that areas of increased ChAT+ cell density often corresponded to the positions of enkephalin-rich patches within the dorsal-lateral caudate nucleus. At more ventral regions, there was no clear correspondence between areas of increased ChAT+ cell density and enkephalin-rich patches. In agreement with these observations, a quantitative analysis of sections double-labeled for ChAT and enkephalin revealed that the density of cholinergic neurons within enkephalin-rich patches was twice that in the surrounding tissue in the dorsal region of the caudate nucleus. In contrast at more ventral levels, the difference in the density of ChAT+ cells in enkephalin-rich patches did not significantly differ from that in the surrounding striatal tissue. Both the results of the 3-D and the double-labeling analysis suggest that cholinergic neurons are not evenly distributed within the caudate nucleus of the cat but form loose clusters which are associated dorsally with the enkephalin-rich patches. These results also provide further evidence of heterogeneity within the striosomal compartment in the cat.

Animals↗
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

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↗