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PubMed1996

Global brain ischemia and reperfusion.

Brain damage accompanying cardiac arrest and resuscitation is frequent and devastating. Neurons in the hippocampus CA1 and CA4 zones and cortical layers III and V are selectively vulnerable to death after injury by ischemia and reperfusion. Ultrastructural evidence indicates that most of the structural damage is associated with reperfusion, during which the vulnerable neurons develop disaggregation of polyribosomes, peroxidative damage to unsaturated fatty acids in the plasma membrane, and prominent alterations in the structure of the Golgi apparatus that is responsible for membrane assembly. Reperfusion is also associated with vulnerable neurons with prominent production of messenger RNAs for stress proteins and for the proteins of the activator protein-1 complex, but these vulnerable neurons fail to efficiently translate these messages into the proteins. The inhibition of protein synthesis during reperfusion involves alteration of translation initiation factors, specifically serine phosphorylation of the alpha-subunit of eukaryotic initiation factor-2 (elF-2 alpha). Growth factors--in particular, insulin--have the potential to reverse phosphorylation of elF-2 alpha, promote effective translation of the mRNA transcripts generated in response to ischemia and reperfusion, enhance neuronal defenses against radicals, and stimulate lipid synthesis and membrane repair. There is now substantial evidence that the insulin-class growth factors have neuron-sparing effects against damage by radicals and ischemia and reperfusion. This new knowledge may provide a fundamental basis for a rational approach to "cerebral resuscitation" that will allow substantial amelioration of the often dismal neurologic outcome now associated with resuscitation from cardiac arrest.

Brain Ischemia↗

PubMed2003

Spatial resolution of phospholipid scramblase 1 (PLSCR1), caspase-3 activation and DNA-fragmentation in the human hippocampus after cerebral ischemia.

Reports on non-neural cells have shown that enhanced activity of the Ca(2+)-dependent/ATP-independent phospholipid scramblase (PLSCR1) is, at least in part, responsible for surface exposure of phosphatidylserine and the collapse of plasma membrane asymmetry in injured or apoptotic cells. To shed some light on mechanisms with a potential to lead to apoptotic death of human neurones following ischemic/hypoxic injury, we examined the immunoreactivity of hippocampal neurones for PLSCR1, caspase-3, cytochrome c and DNA-fragmentation in 22 individuals with clinically symptomatic cerebral ischemia after cardiac arrest or severe hypotension. WE FOUND: (1) significant differences in the percentage of PLSCR1-immunoreactive neurones between controls and short survivors; statistically strong differences between the frequency of immunoreactive neurones among the subfields studied with lowest levels in the CA3; preferential distribution of immunoreactive neurones in controls within the regio entorhinalis, subfield CA1, and hilum. Additionally, these areas exhibited staining of fibre bundles which probably correspond to perforant path, alvear path and collateral's of Schaffer, (2) caspase-3 was upregulated in a region-specific manner with marked activation in the selectively vulnerable hippocampal areas, (3) cytochrome c was redistributed, (4) DNA-fragmentation represented by scattered TUNEL-positive cells increased predominantly during the first 3 days after ischemia, and particularly in the regions of greatest susceptibility to hypoxic injury. This study presents the first evidence that PLSCR1, and probably remodelling of plasma membrane phospholipids (PL), plays a role in ischemic injury in the human hippocampus.

Adult↗

PubMed2003

Post-ischemic activation of caspase-3 in the rat hippocampus: evidence of an axonal and dendritic localisation.

The relationship between caspase-3 activation and delayed neuronal death after ischemia was examined. Expression of caspase-3 was evaluated by colorimetric assay, immunoblotting and by immunohistochemistry. Apoptosis was characterised by terminal desoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labelling. Immunohistochemistry showed caspase-3 activation in the whole hippocampus as early as 30 min after ischemia with exclusive localisation in fiber systems, especially in the perforant path and mossy fibers, Schaffer-collaterals, as well as apical and basal dendrites of pyramidal cells. One day post-ischemia, the 18 kDa cleavage product of caspase-3 (p18) was seen in all cell compartments (nucleus, cytosol and dendrites) throughout the entire subfields and the dentate gyrus with high distribution in mossy fibers. Two days post-ischemia, p18 kDa was only seen in the nuclei and cytosol of hippocampal cells without specific regional differences among hippocampal subfields. A significant number of apoptotic cells appeared only in the CA1 pyramidal cells at 2-3 days post-ischemia. Our data provides the first evidence that caspase-3 activation was detectable in the trisynaptic pathway fiber bundles which probably correspond to perforant path, alvear path and collaterals of Schaffer, and that activation of caspase-3 led to execution of apoptotic cell death program in selectively vulnerable areas, but not in the resistant area of the hippocampus.

Animals↗

PubMed2003

Implication of ionotropic glutamate receptors in the release of noradrenaline in hippocampal CA1 and CA3 subregions under oxygen and glucose deprivation.

A strong linkage between adrenergic and glutamatergic systems exists in the CNS but it is still unclear whether the excessive release of noradrenaline under ischemic conditions is modulated by excitatory amino acids. We studied the effect of selective glutamate receptor antagonists on the release of [3H]noradrenaline evoked by glucose and oxygen deprivation in hippocampal CA1, CA3 and dentate gyrus subregions. The release of glutamate, aspartate and GABA was measured by HPLC. Omission of oxygen and glucose increased the release of [3H]noradrenaline as well as the release of amino acids. Maximum effect on noradrenaline release was observed in CA1 region. The relative increase of the release after 30 min energy deprivation (R(2)) versus the basal release under normal conditions (R(1)), i.e. the R(2)/R(1) ratio was 7.1+/-1.0, 3.87+/-0.4 and 3.26+/-0.27 for CA1, CA3 and dentate gyrus, respectively. The [3H]noradrenaline outflow in response to glucose and oxygen deprivation was abolished at low temperature, but not by Ca(2+) removal, suggesting a cytoplasmic release process. In CA1 and CA3 [3H]noradrenaline release was significantly attenuated by MK-801, an NMDA receptor antagonist. The AMPA receptor antagonist GYKI-53784 had no effect in CA3, but partly reduced noradrenaline release in CA1. Our results suggest that ionotropic glutamate receptors seem to be implicated in the massive cytoplasmic release of noradrenaline in CA1 what may contribute to its selective vulnerability.

Animals↗

PubMed2000

The alpha-ketoglutarate dehydrogenase complex in neurodegeneration.

Altered energy metabolism is characteristic of many neurodegenerative disorders. Reductions in the key mitochondrial enzyme complex, the alpha-ketoglutarate dehydrogenase complex (KGDHC), occur in a number of neurodegenerative disorders including Alzheimer's Disease (AD). The reductions in KGDHC activity may be responsible for the decreases in brain metabolism, which occur in these disorders. KGDHC can be inactivated by several mechanisms, including the actions of free radicals (Reactive Oxygen Species, ROS). Other studies have associated specific forms of one of the genes encoding KGDHC (namely the DLST gene) with AD, Parkinson's disease, as well as other neurodegenerative diseases. Reductions in KGDHC activity can be plausibly linked to several aspects of brain dysfunction and neuropathology in a number of neurodegenerative diseases. Further studies are needed to assess mechanisms underlying the sensitivity of KGDHC to oxidative stress and the relation of KGDHC deficiency to selective vulnerability in neurodegenerative diseases.

Brain↗

PubMedDate not supplied

Substance P and somatostatin content and transport in the vagus and sciatic nerves of the aging Fischer 344 rat.

The two widely distributed neuropeptides, substance P (SP) and somatostatin (SS), are synthesized in cell bodies of the sensory ganglia of the vagus and sciatic nerves and transported bidirectionally toward the central nervous system and sites of sensory innervation. In this study, the content of both peptides was measured in the vagus and sciatic nerves of Fischer 344 rats aged 4, 12 and 25 months. In addition, as an indicator of biosynthesis within the sensory ganglia, the quantity of neuropeptide transported during 22 hours in a peripheral orthograde direction was measured using the ligation technique in animals age 12, 18 and 25 months. The content and transported quantity of SP was unchanged or slightly increased in both nerves as a function of age. Somatostatin content was unchanged and transport increased in the vagus of older rats. In contrast, in the sciatic nerve, SS content was reduced by more than 30% in older rats (p less than 0.01); transported somatostatin was proportionately reduced (p less than 0.05). These findings demonstrate that neuropeptide levels in the sensory vagus are not reduced as a function of age. Somatostatinergic dorsal root ganglion neurons may be selectively vulnerable in the aging Fischer rat.

Aging↗

PubMed1998

Plasticity in adult and ageing sympathetic neurons.

The nature of neural plasticity and the factors that influence it vary throughout life. Adult neurons undergo extensive and continual adaptation in response to demands that are quite different from those of early development. We review the main influences on the survival, growth and neurotransmitter expression in adult and ageing sympathetic neurons, comparing these influences to those at work in early development. This "developmental" approach is proposed because, despite the contrasting needs of different phases of development, each phase has a profound influence on the mechanisms of plasticity available to its successors. Interactions between neurons and their targets, whether effector cells or other neurons, are vital to all of these aspects of neural plasticity. Sympathetic neurons require access to target-derived diffusible neurotrophic factors such as NGF, NT3 and GDNF, as well as to bound elements of the extracellular matrix such as laminin. These factors probably influence plasticity throughout life. In adult life, and even in old age, sympathetic neurons are relatively resistant to cell death. However, they continue to require target-derived diffusible and bound factors for their maintenance, growth and neurotransmitter expression. Failure to maintain appropriate neuronal function in old age, for example in the breakdown of homeostasis, may result partly from a disturbance of the dynamic, trophic relationship between neurons and their targets. However, there is no clear evidence that this is due to a failure of targets to synthesize neurotrophic factors. On the neural side of the equation, altered responsiveness of sympathetic neurons to neurotrophic factors suggests that expression of the trk and p75 neurotrophin receptors contributes to neuronal survival, maintenance and growth in adulthood and old age. Altered receptor expression may therefore underlie the selective vulnerability of some sympathetic neurons in old age. The role of neural connectivity and activity in the regulation of synthesis of target-derived factors, as well as in neurotransmitter dynamics, is reviewed.

Adult↗

PubMed2000

Differential sensitivity of rat hippocampal and cortical astrocytes to oxygen-glucose deprivation injury.

Selective vulnerability of hippocampal neurons to ischemia is felt to relate to intense glutamatergic input and glutamate receptor expression. Since astrocytes are thought to have a neuroprotective role we speculated that hippocampal astrocyte sensitivity to insult could also contribute to this regional vulnerability. The purpose of the study was to determine if there is a differential sensitivity of cultured hippocampal and cortical astrocytes to oxygen-glucose deprivation (OGD). Hippocampal and cortical astrocytes were grown to confluence at matching cell density. Cultures were exposed to OGD for 2, 4, 6, 8 and 10 h. Progressive reduction in viability occurred in hippocampal astrocytes beginning at 2 h OGD. Reduction in cortical astrocyte viability was not observed until 4 h OGD. Death of hippocampal astrocytes was significantly greater than that of cortical astrocytes at each period of OGD. Based on acid phosphatase activity data the LD(50) for OGD duration in hippocampal astrocytes was 2 h compared to 8 h in cortical astrocytes. Regional differences in sensitivity of astrocytes to OGD implies that this may contribute to regional differences in neuronal vulnerability to ischemia.

Acid Phosphatase↗

PubMed2001

Regional distribution of ethanolamine plasmalogen in the hippocampal CA1 and CA3 regions and cerebral cortex of the gerbil.

Although ethanolamine plasmalogens (EtnPm) are the predominant phospholipids in neural tissue, their physiological role has not been clarified. The biophysical conformation of EtnPm in the proteoliposome enhances the activity of the sodium-calcium exchanger, which has been proposed to induce intracellular calcium ion accumulation during ischemia and early reperfusion. The levels of EtnPm in the areas of the gerbil brain selectively vulnerable to ischemia, namely the hippocampal CA1 and CA3 regions and the cerebral cortex, were measured by high-performance thin-layer chromatography and gas-liquid chromatography. The concentration of EtnPm in the CA1 region, which is the most vulnerable to ischemic and anoxic stress, was 2.6- and 2.7-fold higher than that in the CA3 region and cerebral cortex, respectively. The significantly higher concentration of EtnPm in the hippocampal CA1 region may enhance sodium-calcium exchanger activity and play an important role in the vulnerability of this region to ischemia.

Animals↗

PubMed2003

CCAAT/enhancer binding proteins are expressed in the gerbil hippocampus after transient forebrain ischemia.

We analyzed CCAAT/enhancer binding protein (C/EBP) family protein levels during reperfusion after a single episode of sublethal forebrain ischemia in the gerbil hippocampus to investigate their expression after ischemia and correlation with neuronal cell death. The common carotid arteries were surgically exposed bilaterally and occluded for 10 min to induce forebrain ischemia in adult Mongolian gerbils. C/EBPalpha, beta, delta, epsilon, zeta protein immunoreactivity was expressed in the hippocampal layer of the CA1 region at 72 h after ischemia and peaked at 96 h. These results appear to correlate with neuronal degeneration as shown by hematoxylin and eosin staining and DNA fragmentation in the terminal transferase biotinylated-UTP nick end labeled-method. The present results demonstrate that C/EBP family proteins appear in the selectively vulnerable CA1 pyramidal cell layer in gerbils during neuronal degeneration, and may serve as a signal that neurons are progressing to neuronal cell death and DNA fragmentation.

Animals↗

PubMed1996

The pyramidal cell layer of sector CA 1 shows the lowest hippocampal succinate dehydrogenase activity in normal and postischemic gerbils.

We examined regional differences in the activity of a mitochondrial respiratory enzyme, succinic dehydrogenase (SDH), in the hippocampi of normal and postischemic gerbils, using a quantitative imaging method. Gerbils (n = 21) without ischemia, and gerbils which had experienced 5 min of bilateral common carotid artery occlusion 12 h or 2 days previously, were sacrificed. Coronal sections of the brains were prepared for quantitative imaging of SDH activity and histological examination. In the control gerbils, SDH activity in the pyramidal cell layer of the CA 1 sector (Sommer's sector) was 106.3 +/- 10.3% (mean +/- SD; SDH activity as a percentage of the cerebellar SDH activity), which was lower than in the other subfields of the hippocampus. SDH activity in the oriens layer, stratum radiatum and lacunosum molecular layer of the CA 1 sector was lower than in the corresponding layers of the CA 2 and CA 3 sectors. After transient ischemia, SDH activity remained unchanged in the CA 1 sector. Histologically, selective neuronal necrosis was observed in the pyramidal cell layer of the CA 1 sector 2 days after ischemia. The observed low level of this mitochondrial respiratory enzyme in the pyramidal cell layer of the CA 1 sector should be taken into account as a possible trigger of the selective vulnerability of the region to ischemia.

Animals↗

PubMed1997

Beta-amyloid induced increase in choline flux across PC12 cell membranes.

Beta-amyloid peptide is the main constituent of senile plaques and is implicated in the pathogenesis of Alzheimer's disease. It has been shown to be both neurotoxic and neurotrophic in vivo, and its effects have been suggested to be mediated in part by alterations in membrane transport. In the present study, we investigated the effect of beta-amyloid (1-40) on choline transport in cultured PC12 cells. We found that exposure to 46 or 92 microM beta-amyloid (1-40) increased [14C]choline flux in PC12 cells in a concentration-dependent manner, whereas exposure to reverse sequence beta-amyloid (40-1) had no effect. If there is a similar effect in vivo, the increased beta-amyloid dependent permeability to choline could lead to depletion of cellular choline stores and could contribute to the selective vulnerability of cholinergic neurons in Alzheimer's disease.

Alzheimer Disease↗

PubMed1997

Neuronal injury in experimental status epilepticus in the rat: role of hypoxia.

While it seems axiomatic that hypoxia is a risk factor for neuronal death during prolonged seizures, the classic neuropathologic literature does not confirm such an association. We investigated this issue by inducing status epilepticus in normoxic (PaO2 approximately 100 mmHg) and hypoxia (PaO2 approximately 50 mmHg) rats, using heat-shock protein (HSP) expression as an index of early cell injury and acid fuchsin staining to detect cell death. Neither stress protein induction nor neuronal death was increased in the selectively vulnerable CA3c region of hippocampus, or in cerebral cortex, of hypoxic compared to normoxic animals. These data support the concept that moderate hypoxia is not a risk factor for brain injury from status epilepticus.

Animals↗

PubMed1998

Influence of neonatal focal cerebral hypoxia-ischemia on cardiovascular and neurobehavioral functions in adult Wistar rats.

No experimental studies looked at the disturbances appearing after a neonatal focal cerebral hypoxia-ischemia (HI) when animals become adults. Using radiotelemetry, we examined the effects of neonatal focal cerebral HI on blood pressure (BP), heart rate (HR), locomotor activity (LA), body temperature (BT) levels and circadian rhythm parameters of unrestrained adult Wistar rats. At 15 weeks of age, we continuously recorded the cardiovascular and neurobehavioral parameters of HI (n = 6) and sham-operated (n = 6) rats. In adult rats, HI induced persistent hypertensive effects associated with alteration in BP circadian rhythms and pronounced decreases in mesor and percent rhythm of LA. HR and BT parameters were not significantly modified. Therefore, our results suggest that the rat cardiovascular and behavioural circadian control systems may involve several structures which present selective vulnerability to early cerebral HI.

Animals↗

PubMed2000

Nitric oxide reduces Ca(2+) and Zn(2+) influx through voltage-gated Ca(2+) channels and reduces Zn(2+) neurotoxicity.

The translocation of synaptic Zn(2+) from nerve terminals into selectively vulnerable neurons may contribute to the death of these neurons after global ischemia. We hypothesized that cellular Zn(2+) overload might be lethal for reasons similar to cellular Ca(2+) overload and tested the hypothesis that Zn(2+) neurotoxicity might be mediated by the activation of nitric oxide synthase. Although Zn(2+) (30-300microM) altered nitric oxide synthase activity in cerebellar extracts in solution, it did not affect nitric oxide synthase activity in cultured murine neocortical neurons. Cultured neurons exposed to 300-500microM Zn(2+) for 5min under depolarizing conditions developed widespread degeneration over the next 24h that was unaffected by the concurrent addition of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine. Furthermore, Zn(2+) neurotoxicity was attenuated when nitric oxide synthase activity in the cultures was induced by exposure to cytokines, exogenous nitric oxide was added or nitric oxide production was pharmacologically enhanced. The unexpected protective effect of nitric oxide against Zn(2+) toxicity may be explained, at least in part, by reduction of toxic Zn(2+) entry. Exposure to nitric oxide donors reduced Ba(2+) current through high-voltage activated calcium channels, as well as K(+)-stimulated neuronal uptake of 45Ca(2+) or 65Zn(2+). The oxidizing agents thimerosal and 2,2'-dithiodipyridine also reduced K(+)-stimulated cellular 45Ca(2+) uptake, while akylation of thiols by pretreatment with N-ethylmaleimide blocked the reduction of 45Ca(2+) uptake by a nitric oxide donor.The results suggest that Zn(2+)-induced neuronal death is not mediated by the activation of nitric oxide synthase; rather, available nitric oxide may attenuate Zn(2+) neurotoxicity by reducing Zn(2+) entry through voltage-gated Ca(2+) channels, perhaps by oxidizing key thiol groups.

Animals↗

PubMed2002

Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease.

Amyloid beta(1-42), a major component of amyloid plaques, binds with exceptionally high affinity to the alpha 7 nicotinic acetylcholine receptor and accumulates intracellularly in neurons of Alzheimer's disease brains. In this study, we investigated the possibility that this binding plays a key role in facilitating intraneuronal accumulation of amyloid beta(1-42). Consecutive section immunohistochemistry and digital imaging were used to reveal the spatial relationship between amyloid beta(1-42) and the alpha 7 receptor in affected neurons of Alzheimer's disease brains. Results showed that neurons containing substantial intracellular accumulations of amyloid beta(1-42) invariably express relatively high levels of the alpha 7 receptor. Furthermore, this receptor is highly co-localized with amyloid beta(1-42) within neurons of Alzheimer's disease brains. To experimentally test the possibility that the binding interaction between exogenous amyloid beta(1-42) and the alpha 7 receptor facilitates internalization and intracellular accumulation of amyloid beta(1-42) in Alzheimer's disease brains, we studied the fate of exogenous amyloid beta(1-42) and its interaction with the alpha 7 receptor in vitro using cultured, transfected neuroblastoma cells that express elevated levels of this receptor. Transfected cells exhibited rapid binding, internalization and accumulation of exogenous amyloid beta(1-42), but not amyloid beta(1-40). Furthermore, the rate and extent of amyloid beta(1-42) internalization was related directly to the alpha 7 receptor protein level, since (1) the rate of amyloid beta(1-42) accumulation was much lower in untransfected cells that express much lower levels of this receptor and (2) internalization was effectively blocked by alpha-bungarotoxin, an alpha 7 receptor antagonist. As in neurons of Alzheimer's disease brains, the alpha 7 receptor in transfected cells was precisely co-localized with amyloid beta(1-42) in prominent intracellular aggregates. Internalization of amyloid beta(1-42) in transfected cells was blocked by phenylarsine oxide, an inhibitor of endocytosis. We suggest that the intraneuronal accumulation of amyloid beta(1-42) in Alzheimer's disease brains occurs predominantly in neurons that express the alpha 7 receptor. In addition, internalization of amyloid beta(1-42) may be facilitated by the high-affinity binding of amyloid beta(1-42) to the alpha 7 receptor on neuronal cell surfaces, followed by endocytosis of the resulting complex. This provides a plausible explanation for the selective vulnerability of neurons expressing the alpha 7 receptor in Alzheimer's disease brains and for the fact that amyloid beta(1-42) is the dominant amyloid beta peptide species in intracellular accumulations and amyloid plaques.

Aged↗

PubMed2003

Ventral root avulsion leads to downregulation of GluR2 subunit in spinal motoneurons in adult rats.

It has been observed that motor neuron death is induced in adult rats by ventral root avulsion which involves pulling out the spinal cord root. Since motor neurons are reported to be selectively vulnerable to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor-mediated injury in vitro, we investigated changes in the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-receptor subunits in rat spinal motor neurons after ventral root avulsion. The L4-L5 ventral roots of adult Sprague-Dawley rats were avulsed by an extravertebral extraction procedure. After an appropriate survival time, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-receptor subunits were detected immunohistochemically in the L4-L5 segments. Ventral root avulsion resulted in a 60% loss of motor neurons by 14 days after surgery. GluR2 labeling in motor neurons was markedly decreased after avulsion, but before the onset of motor neuron death, while the GluR1 and GluR4 labeling of motor neurons remained unchanged. Intrathecal administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-receptor antagonists rescued a significant number of injured motor neurons from cell death. In contrast, N-methyl-D-aspartate-receptor antagonists did not prevent motor neuron death. Since the presence of GluR2 subunit renders heteromeric alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors Ca(2+)-impermeable, the downregulation of GluR2 may result in increased formation of GluR2-lacking, Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors in motor neurons and could contribute to motor neuron death after ventral root avulsion.

Animals↗

PubMed2003

Biochemical analysis of GABA(A) receptor subunits alpha 1, alpha 5, beta 1, beta 2 in the hippocampus of patients with Alzheimer's disease neuropathology.

Alzheimer's disease (AD) is characterized by selective vulnerability of specific neuronal populations within particular brain regions. For example, hippocampal glutamatergic cell populations within the CA1/subicular pyramidal cell fields have been found to be particularly vulnerable early in AD progression. In contrast, hippocampal GABA-ergic neurons and receptors appear resistant to neurodegeneration. Despite relative sparing of GABA(A) receptors in AD, it is possible that the specific subunit composition of these receptors may undergo alterations with disease progression. In order to address this issue, we employed quantitative Western blot analysis to examine protein levels of GABA(A) receptor subunits alpha 1, alpha 5, beta 1, beta 2 in the hippocampus of subjects displaying increasing severity of AD neuropathology. Subjects were categorized into three groups based upon Braak staging pathologic criteria: pathologically mild (stages I/II, n=9); moderate (stages III/IV, n=8); and severe (stages V/VI, n=7). Across all subject groups, levels of subunit protein were heterogeneously distributed throughout the five hippocampal subregions analyzed (subiculum, CA1-3, dentate gyrus). Statistical analyses revealed differential preservation of GABA(A) receptor subunits in AD. In particular, alpha 1, beta 1, and beta 2 displayed little difference in protein levels among pathologically mild, moderate, and severe subject groups. In contrast, although relatively modest, protein levels of the alpha 5 subunit were significantly reduced between subjects with severe neuropathology compared with pathologically mild subjects (13.5% reduction). Collectively, our data provide evidence for heterogeneous distribution and relative sparing of GABA(A) receptor subunits in the hippocampus of AD patients.

Aged↗