Dehua Chui

Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.

Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of Aβ1–42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited Aβ42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.

Stress induces neuronal death in the hippocampus of castrated rats.

Whereas loss of CA3 neurons in the hippocampus of monkeys which died of stress ulcers suggests that some structural changes may occur, there is no direct evidence that shows stress-induced irreversible changes of neurons. When rats were orchidectomized (castrated) and stressed by restraint and immersion in water for 15 min/day for 30 days, significant loss of hippocampal CA3 and CA4 neurons was observed. Furthermore, primary cultured hippocampal neurons survived shorter when treated with corticosterone. This neuronal loss was prevented by simultaneous administration of testosterone in vivo and in vitro. These findings indicate that stress can contribute to neuronal degeneration associated with hypogonadal conditions such as aging.

Astrocytes: Implications for Neuroinflammatory Pathogenesis of Alzheimers Disease

Alzheimers disease (AD) is a neurodegenerative disease with major clinical hallmarks of memory loss, dementia, and cognitive impairment. Neuroinflammation is involved in the onset of several neurodegenerative disorders. Astrocyte is the most abundant type of glial cells in the central nervous system (CNS) and appears to be involved in the induction of neuroinflammation. Under stress and injury, astrocytes become astrogliotic leading to an upregulation of the expression of proinflammatory cytokines and chemokines, which are associated with the pathogenesis of AD. Cytokines and related molecules play roles in both neuroprotection and neurodegeneration in the CNS. During early AD pathogenesis, amyloid beta (Aβ), S100B and IL-1β could bring about a vicious cycle of Aβ generation between astrocytes and neurons leading to chronic, sustained and progressive neuroinflammation. In advanced stages of AD, TRAIL secreted from astrocytes have been shown to bind to death receptor 5 (DR5) on neurons to trigger apoptosis in a caspase-8-dependent manner. Furthermore, astrocytes could be reactivated by TGFβ1 to generate more Aβ and to undergo the aggravating astrogliosis. TGFβ2 was also observed to cooperate with Aβ to cause neuronal demise by destroying the stability of lysosomes in neurons. Inflammatory molecules can be either potential biomarkers for diagnosis or target molecules for therapeutic intervention. Understanding their roles and their relationship with activated astrocytes is particularly important for attenuating neuroinflammation in the early stage of AD. The main purpose of this review is to provide a comprehensive insight into the role of astrocytes in the neuroinflammatory pathogenesis of AD.

Chronic stress differentially regulates glucocorticoid negative feedback response in rats

Exposure to chronic stress is thought to play an important role in the etiology of depression. In this disorder, a disrupted negative feedback response to exogenous glucocorticoids on cortisol secretion has been indicated. However, the regulation of glucocorticoid negative feedback by chronic stress is not fully understood. In the present study, we investigated the effects of chronic stress administered by water immersion and restraint (2 h/day) for four weeks on the glucocorticoid feedback in rats. In the acutely (one-time) stressed rats, the basal plasma corticosterone (CORT) level was markedly elevated, remained at high levels for 5 h after the termination of stress, and then decreased. In the chronically stressed rats, the CORT level was initially elevated similarly, but rapidly decreased at 2 h. In the dexamethasone (DEX) suppression test, the peak CORT level in response to stress was not suppressed by DEX in the acutely stressed rats, but was significantly suppressed in the chronically stressed rats. In contrast, the suppressive effects of DEX on the basal CORT secretion in naive rats were attenuated in the chronically stressed rats. In the chronically stressed hippocampus, which plays an important role in the regulation of the glucocorticoid feedback response, the binding of [3H]DEX was decreased and the increased response of activator protein-1 induced by acute stress was abolished. These results suggest that chronic stress induces a hypersuppressive state for induced CORT secretion in response to acute stress, which is caused by partial habituation, coping, and adaptation to the stressor, whereas it induces a hyposuppressive state for the basal CORT secretion, which is caused by glucocorticoid receptor downregulation. These mechanisms may be involved in the stress-induced neural abnormalities observed in depression.

Apoptotic neurons in Alzheimer's disease frequently show intracellular Aβ42 labeling

It is widely accepted that Abeta plays a pivotal role in the pathogenesis of Alzheimers disease (AD) [27]. Attention has been focused mainly on how extracellular Abeta exerts its effects on neuronal cells [7,11,16,32]. However, neuronal degeneration from an accumulation of intracellular Abetax-42 (iAbeta42) occurs in presenilin 1 (PS1) mutant mice without extracellular Abeta deposits [5]. In the present study, intracellular deposits of iAbeta42 are correlated with apoptotic cell death in AD and PS-1 familial AD (PS1 FAD) brains by means of triple staining with antibodies to Abeta, TUNEL, and staining with Hoechst 33342. Neurons simultaneously positive for iAbeta42 and the TUNEL assay were significantly more abundant in AD brains than in controls. The number of apoptotic neurons with intracellular neurofibrillary tangles (iNFTs) was insignificant. Our results indicate that intraneuronal deposition of a neurotoxic form of Abeta seems to be an early event in the neurodegeneration of AD.

Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer’s disease mouse model

BackgroundProfound synapse loss is one of the major pathological hallmarks associated with Alzheimer’s disease, which might underlie memory impairment. Our previous work demonstrates that magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we tested whether elevation of brain magnesium, using a recently developed compound (magnesium-L-threonate, MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic mouse model of Alzheimer’s disease.ResultsMgT treatment reduced Aβ-plaque, prevented synapse loss and memory decline in the transgenic mice. Strikingly, MgT treatment was effective even when the treatment was given to the mice at the end-stage of their Alzheimer’s disease-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brain of transgenic mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the transgenic mice, the NMDAR signaling pathway was downregulated, while the BACE1 expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression and reduced sAPPβ and β-CTF in the transgenic mice. At the molecular level, elevation of extracellular magnesium prevented the high Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices.ConclusionsOur results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of Alzheimers disease, and hence it might have therapeutic potential for treating Alzheimers disease.

Glypican-1 as an Aβ binding HSPG in the human brain: its localization in DIG domains and possible roles in the pathogenesis of Alzheimer’s disease

Previous studies have suggested that heparan sulfate proteoglycans (HSPGs) play a role in deposition of β‐amyloid protein (Aβ) in the Alzheimers disease (AD) brain. In the present study, we demonstrated that glypican‐1 can bind fibrillar Aβ, and the binding is mainly mediated by heparan sulfate (HS) chains. Further analysis revealed that glypican‐1 is the major HSPG localized in detergent‐insoluble glycosphingolipid‐enriched (DIG) domains where all machineries for Aβ production exist and Aβ is accumulated as monomeric and oligomeric forms. Immunohistochemical studies demonstrated that glypican‐1 is localized in primitive plaques as well as classic plaques. Moreover, overexpression of glypican‐1 and amyloid precursor protein in SH‐SY5Y cells resulted in reduced cell viability and made cells more susceptible to thapsigargin‐induced stress and Aβ toxicity. The results raise the possibility that glypican‐1 interacts with oligomerized or polymerized Aβ in such a specific compartment as DIG, resulting not only in amyloid deposition in senile plaques of AD brain, but also in accelerating neuronal cell death in response to stress and Aβ.

Both N-terminal and C-terminal fragments of Presenilin 1 colocalize with neurofibrillary tangles in neurons and dystrophic neurites of senile plaques in Alzheimer's disease

Presenilin 1 (PS1) is a causative gene for chromosome 14‐linked familial Alzheimers disease. The gene product is known to be cleaved into N‐terminal fragments (PS1‐N) and C‐terminal fragments (PS1‐C). To understand the pathophysiological role of PS1, we conducted immunohistochemical studies using antibodies specific for PS1‐N and PS1‐C in sporadic Alzheimers disease (AD). Both antibodies showed punctuate staining exclusively in neurons and their processes in both control and AD brains. PS1‐N immunolabeling colocalized with neurofibrillary tangles (NFTs) in 36% of NFT‐bearing neurons and with dystrophic neurites in 28% of senile plaques (SPs). PS1‐C immunolabeling colocalized with dystrophic neurites in 70% of NFT‐bearing SPs and with intraneuronal NFTs in 32% of NFT‐bearing neurons. Both antibodies did not detect PHF‐tau‐positive neuropil threads and Aβ amyloid fibrils. The colocalization was also found in 33–38% of NFT‐bearing neurons in progressive supranuclear palsy. These results indicate that both PS1‐N and PS1‐C fragments are deposited in part of NFT‐bearing neurons and dystrophic neurites in SPs; both are the pathologic hallmarks of AD. J. Neurosci. Res. 53:99–106, 1998.

Presynaptic defects underlying impaired learning and memory function in lipoprotein lipase-deficient mice.

Lipoprotein lipase (LPL) is predominantly expressed in adipose and muscle where it plays a crucial role in the metabolism of triglyceride-rich plasma lipoproteins. LPL is also expressed in the brain with highest levels found in the pyramidal cells of the hippocampus, suggesting a possible role for LPL in the regulation of cognitive function. However, very little is currently known about the specific role of LPL in the brain. We have generated a mouse model of LPL deficiency which was rescued from neonatal lethality by somatic gene transfer. These mice show no exogenous and endogenous LPL expression in the brain. To study the role of LPL in learning and memory, the performance of LPL-deficient mice was tested in two cognitive tests. In a water maze test, LPL-deficient mice exhibited increased latency to escape platform and increased mistake frequency. Decreased latency to platform in the step-down inhibitory avoidance test was observed, consistent with impaired learning and memory in these mice. Transmission electron microscopy revealed a significant decrease in the number of presynaptic vesicles in the hippocampus of LPL-deficient mice. The levels of the presynaptic marker synaptophysin were also reduced in the hippocampus, whereas postsynaptic marker postsynaptic density protein 95 levels remained unchanged in LPL-deficient mice. Theses findings indicate that LPL plays an important role in learning and memory function possibly by influencing presynaptic function.

Activation of the canonical nuclear factor-κB pathway is involved in isoflurane-induced hippocampal interleukin-1β elevation and the resultant cognitive deficits in aged rats.

Although much recent evidence has demonstrated that neuroinflammation contributes to volatile anesthetic-induced cognitive deficits, there are few existing mechanistic explanations for this inflammatory process. This study was conducted to investigate the effects of the volatile anesthetic isoflurane on canonical nuclear factor (NF)-κB signaling, and to explore its association with hippocampal interleukin (IL)-1β levels and anesthetic-related cognitive changes in aged rats. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in IκB kinase and IκB phosphorylation, as well as a reduction in the NF-κB inhibitory protein (IκBα), were observed in the hippocampi of isoflurane-exposed rats compared with control rats. These events were accompanied by an increase in NF-κB p65 nuclear translocation at 6h after isoflurane exposure and hippocampal IL-1β elevation from 1 to 6h after isoflurane exposure. Nevertheless, no significant neuroglia activation was observed. Pharmacological inhibition of NF-κB activation by pyrrolidine dithiocarbamate markedly suppressed the IL-1β increase and NF-κB signaling, and also mitigated the severity of cognitive deficits in the Morris water maze task. Overall, our results demonstrate that isoflurane-induced cognitive deficits may stem from upregulation of hippocampal IL-1β, partially via activation of the canonical NF-κB pathway, in aged rats.