Alzheimer's disease is recognized post mortem by the presence of extracellular senile plaques, made primarily of aggregation of amyloid β peptide (Aβ). This peptide has consequently been regarded as the principal toxic factor in the neurodegeneration of Alzheimer's disease. As such, intense research effort has been directed at determining its source, activity and fate, primarily with a view to preventing its formation or its biological activity, or promoting its degradation. Clearly, much progress has been made concerning its formation by proteolytic processing of the amyloid precursor protein, and its degradation by enzymes such as neprilysin and insulin degrading enzyme. The activities of Aβ, however, are numerous and yet to be fully elucidated. What is currently emerging from such studies is a diffuse but steadily growing body of data that suggests Aβ has important physiological functions and, further, that it should only be regarded as toxic when its production and degradation are imbalanced. Here, we review these data and suggest that physiological levels of Aβ have important physiological roles, and may even be crucial for neuronal cell survival. Thus, the view of Aβ being a purely toxic peptide requires re-evaluation.
The amyloid beta peptide (Abeta) is a product of the sequential gamma- and beta-secretase cleavage of amyloid precursor protein. Inhibitors of secretase enzymes have been proposed as a potential therapeutic strategy in the treatment of Alzheimer's disease. Here, we investigate the effect of inhibiting these key enzymes on the viability of a range of cell types. Treatment of rat cortical neurons for 24 hr with secretase inhibitors or an antibody that binds Abeta resulted in a marked reduction in cell viability, as measured by MTT reduction. Incubation with secretase inhibitors caused similar effects on other neuronal cell types (rat cerebellar granule neurons and the human SH-SY5Y cell line). Interestingly, rat astrocytes and a number of non-neuronal cell lines investigated (HEK293, DDT1-FM2, and human teratorhabdoid tumor cells) were unaffected by incubation with secretase inhibitors. The coincubation of Abeta1-40 prevented the toxicity of secretase inhibitors in neuronal cells. Abeta1-40 was protective in a concentration-dependent manner, and its effects were significant at concentrations as low at 10 pm. Importantly, the protective effects of Abeta were Abeta size-form specific, with the Abeta1-42 size form affording limited protection and the Abeta25-35 size form having very little protective effect. The present study demonstrates that inhibition of beta-or gamma-secretase activity induces death in neuronal cells. Importantly, this toxicity, which our data suggest is a consequence of a decline in neuronal Abeta levels, was absent in non-neuronal cells. This study further supports a key physiological role for the enigmatic Abeta peptide.
Periods of chronic hypoxia, which can arise from numerous cardiorespiratory disorders, predispose individuals to the development of dementias, particularly Alzheimer's disease (AD). AD is characterized in part by the increased production of amyloid beta peptide (Abeta), which forms the extracellular plaques by which the disease can be identified post mortem. Numerous studies have now shown that hypoxia, even in vitro, can increase production of Abeta in different cell types. Evidence has been produced to indicate hypoxia alters both expression of the Abeta precursor, APP, and also the expression of the secretase enzymes, which cleave Abeta from APP. Other studies implicate reduced Abeta degradation as a possible means by which hypoxia increases Abeta levels. Such variability may be attributable to cell-specific responses to hypoxia. Further evidence indicates that some, but not all of the cellular adaptations to chronic hypoxia (including alteration of Ca(2+) homeostasis) require Abeta formation. However, other aspects of hypoxic remodeling of cell function appear to occur independently of this process. The molecular and cellular responses to hypoxia contribute to our understanding of the clinical association of hypoxia and increased incidence of AD. However, it remains to be determined whether inhibition of one or more of the effects of hypoxia may be of benefit in arresting the development of this neurodegenerative disease.
Glutamate uptake by astrocytes is fundamentally important in the regulation of CNS function. Disruption of uptake can lead to excitotoxicity and is implicated in various neurodegenerative processes as well as a consequence of hypoxic/ischemic events. Here, we investigate the effect of hypoxia on activity and expression of the key glutamate transporters excitatory amino acid transporter 1 (EAAT1) [GLAST (glutamate-aspartate transporter)] and EAAT2 [GLT-1 (glutamate transporter 1)]. Electrogenic, Na ϩ -dependent glutamate uptake was monitored via whole-cell patch-clamp recordings from cortical astrocytes. Under hypoxic conditions (2.5 and 1% O 2 exposure for 24 h), glutamate uptake was significantly reduced, and pharmacological separation of uptake transporter subtypes suggested that the EAAT2 subtype was preferentially reduced relative to the EAAT1. This suppression was confirmed at the level of EAAT protein expression (via Western blots) and mRNA levels (via real-time PCR). These effects of hypoxia to inhibit glutamate uptake current and EAAT protein levels were not replicated by desferrioxamine, cobalt, FG0041, or FG4496, agents known to mimic effects of hypoxia mediated via the transcriptional regulator, hypoxia-inducible factor (HIF). Furthermore, the effects of hypoxia were not prevented by topotecan, which prevents HIF accumulation. In stark contrast, inhibition of nuclear factor-B (NF-B) with SN50 fully prevented the effects of hypoxia on glutamate uptake and EAAT expression. Our results indicate that prolonged hypoxia can suppress glutamate uptake in astrocytes and that this effect requires activation of NF-B but not of HIF. Suppression of glutamate uptake via this mechanism may be an important contributory factor in hypoxic/ischemic triggered glutamate excitotoxicity.
-Amyloid protein is thought to underlie the neurodegeneration associated with Alzheimer's disease by inducing Ca 2؉ -dependent apoptosis. Elevated neuronal expression of the proinflammatory cytokine interleukin-1 is an additional feature of neurodegeneration, and in this study we demonstrate that interleukin-1 modulates the effects of -amyloid on Ca 2؉ homeostasis in the rat cortex. -Amyloid-(1-40) (1 M) caused a significant increase in 45 Ca 2؉ influx into rat cortical synaptosomes via activation of L-and N-type voltage-dependent Ca 2؉ channels and also increased the amplitude of N-and P-type Ca 2؉ channel currents recorded from cultured cortical neurons. In contrast, interleukin-1 (5 ng/ml) reduced the 45 Ca 2؉ influx into cortical synaptosomes and inhibited Ca 2؉ channel activity in cultured cortical neurons. Furthermore, the stimulatory effects of -amyloid protein on Ca 2؉ influx were blocked following exposure to interleukin-1, suggesting that interleukin-1 may govern neuronal responses to -amyloid by regulating Ca 2؉ homeostasis.-Amyloid (A-(1-40)) 1 is a peptide fragment derived from proteolytic processing of -amyloid precursor protein (APP) (1), which accumulates as an insoluble extracellular deposit around neurons, giving rise to the senile plaques associated with Alzheimer's disease (AD) (2). Increased neuronal expression of the proinflammatory cytokine interleukin-1 (IL-1) is an additional neuropathological hallmark of AD (3), and inflammatory mediators such as IL-1 have been proposed to contribute to the development of amyloid plaques (4). Several reports describe an interaction between IL-1 and A at the processing level; IL-1-immunoreactive microglia are prominent components of amyloid plaques in AD (4), and -amyloid promotes release of IL-1 by the glial cells that surround senile plaques (5). In turn, IL-1 increases APP mRNA expression (6) and promotes processing of APP to liberate A peptide fragments (7). Thus a chain of events involving IL-1 and A is involved in plaque formation; however, the nature of the interaction between IL-1 and A at a physiological level is poorly understood. Neuronal apoptosis is the suspected causative factor of neurodegeneration in AD, and A fragments have been shown to promote apoptosis in vitro in human-derived neurotypic cells (8) and cultured neurons (9). The mechanism underlying A-induced apoptosis is thought to involve disregulation of Ca 2ϩ homeostasis (10). In the C6 glial cell line, expression of the Ca 2ϩ -binding protein calbindin was found to suppress A-induced apoptosis (11), providing evidence for the involvement of Ca 2ϩ fluxes in A-induced apoptosis. In this study we report that A-(1-40) (i) promotes a stimulation of 45 Ca 2ϩ influx into cortical synaptosomes via activation of L-and N-type voltagedependent Ca 2ϩ channels (VDCCs) and (ii) increases the amplitude of N-and P-type VDCC current in cultured cortical neurons. Furthermore, the A-(1-40)-induced increase in Ca 2ϩ influx is blocked by the proinflammatory mediato...
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