Beta-amyloid, neuronal death and Alzheimer's disease.

Department of Neurology, Medical College of Pennsylvania-Hahnemann University, Philadelphia 19129, USA.
Current Molecular Medicine (Impact Factor: 3.61). 01/2002; 1(6):733-7.
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. Large extracellular beta-amyloid (Abeta) plaques and tau-containing intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective. However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD; the current review summarizes what is known about this issue. Most evidence indicates that amyloid precursor protein (APP) processing is central to the AD process. The Abeta in plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gamma-secretase) enzymatic pathway is utilized for processing. Mutations of the APP gene lead to AD by influencing APP metabolism. One leading theory is that the Abeta in plaques leads to AD because Abeta is directly toxic to the adjacent neurons. Other theories advance the notion that neuronal death is triggered by intracellular events that occur during APP processing or by extraneuronal preplaque Abeta oligomers. Some investigators speculate that in many cases there is a more general disorder of protein processing in neurons that leads to cell death. In the later models, Abeta plaques are a byproduct of the disease process, rather than the direct cause of neuronal death. A direct correlation between Abeta plaque burden and neuronal (or synaptic) loss should occur in AD if Abeta plaques cause AD through a direct toxic effect. However, histopathologic studies indicate that the correlation between Abeta plaque burden and neuronal (or synaptic) loss is poor. We conclude that APP processing and Abeta formation is important to the AD process, but that neuronal alterations that underlie symptoms of AD are not due exclusively to a direct toxic effect of the Abeta deposits that occur in plaques. A more general problem with protein processing, damage due to the neuron from accumulation of intraneuronal Abeta or extracellular, preplaque Abeta may also be important as underlying factors in the dementia of AD.

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    • "Studies have shown that Ab 1–40 is more abundant than Ab 1–42 in AD brain, whereas Ab 1–42 appears more fibrillogenic and toxic than Ab 1–40 [3]. Ab directly induces oxidative stress and causes both apoptotic and necrotic types of neuronal cell death in vitro and in vivo [4] [5]. Since a decade ago, accumulation of Ab has been associated with glaucomatous degeneration of retinal ganglion cell (RGC) [6]. "
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    ABSTRACT: Beta-amyloid (Aβ) derived from amyloid precursor protein (APP) has been associated with retinal degeneration in Alzheimer's disease (AD) and glaucoma. This study examined whether hypoxia exposure induces Aβ accumulation in RGC-5 cells. While levels of APP mRNA and protein significantly increased in the cells, elevated abundance of Aβ was also observed in cells and culture medium between 12 or 24 and 48h after 5% O(2) hypoxia treatment. Additionally, there is a close relationship between induction of APP and Aβ and intracellular accumulation of ROS along with loss of mitochondrial membrane potential followed by the death of RGC-5 cells in culture under hypoxia. These results suggest a possible involvement of APP and Aβ in the death of RGCs challenged by hypoxia.
    Biochemical and Biophysical Research Communications 06/2011; 410(1):40-4. DOI:10.1016/j.bbrc.2011.05.101 · 2.28 Impact Factor
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    • "The most prevalent and costly tauopathy is Alzheimer's disease (AD), in which neurofibrillary tangle pathology is mixed with amyloid plaques. Of these two hallmark features of AD, the amyloid-laden neuritic plaques and metabolites of the amyloid precursor protein (APP) have received extensive scientific attention as causal determinants of dementia and neuropathology (reviewed in Carter and Lippa, 2001; Sinha and Lieberburg, 1999; Wasling et al., 2009). It has been increasingly recognized, however, that neurofibrillary tangle (NFT) pathology contributes to the behavioral consequences of AD (Brunden et al., 2008). "
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    Behavioural brain research 01/2011; 216(1):332-40. DOI:10.1016/j.bbr.2010.08.013 · 3.39 Impact Factor
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    • "Even though amyloid plaques are one of the hallmarks of AD, their exact relationship to the disease remains unclear. Some studies have proposed that the plaques are merely the consequence of other, more precipitous factors; others have suggested that they are central to the disease (reviewed in Carter and Lippa, 2001). The plaques are composed primarily of aggregation of amyloid peptides, which are formed by the proteolytic cleavage of the amyloid precursor protein (APP) by ␤-and ␥-secretases. "
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    ABSTRACT: Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and beta-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.
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