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: 3.62). 01/2002; 1(6):733-7.
Source: PubMed


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 · 2.30 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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    ABSTRACT: Entorhinal cortex neuropathology begins very early in Alzheimer's disease (AD), a disorder characterized by severe memory disruption. Indeed, loss of entorhinal volume is predictive of AD and two of the hallmark neuroanatomical markers of AD, amyloid plaques and neurofibrillary tangles (NFTs), are particularly prevalent in the entorhinal area of AD-afflicted brains. Gene transfer techniques were used to create a model neurofibrillary tauopathy by injecting a recombinant adeno-associated viral vector with a mutated human tau gene (P301L) into the entorhinal cortex of adult rats. The objective of the present investigation was to determine whether adult onset, spatially restricted tauopathy could be sufficient to reproduce progressive deficits in mnemonic function. Spatial memory on a Y-maze was tested for approximately 3 months post-surgery. Upon completion of behavioral testing the brains were assessed for expression of human tau and evidence of tauopathy. Rats injected with the tau vector became persistently impaired on the task after about 6 weeks of postoperative testing, whereas the control rats injected with a green fluorescent protein vector performed at criterion levels during that period. Histological analysis confirmed the presence of hyperphosphorylated tau and NFTs in the entorhinal cortex and neighboring retrohippocampal areas as well as limited synaptic degeneration of the perforant path. Thus, highly restricted vector-induced tauopathy in retrohippocampal areas is sufficient for producing progressive impairment in mnemonic ability in rats, successfully mimicking a key aspect of tauopathies such as AD.
    Behavioural brain research 01/2011; 216(1):332-40. DOI:10.1016/j.bbr.2010.08.013 · 3.03 Impact Factor
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    • "While these observations have implicated Aβ42 in AD, how this polypeptide induces neurodegeneration remains uncertain. The brains of individuals with AD are characterized by large plaques of aggregated Aβ42 protein, neurofibrillary tangles composed of hyperphosphorylated Tau protein, and the loss of a significant fraction of the neurons in the hippocampus, prefrontal and entorhinal cortex [15]–[19]. Initially it was thought that the aggregated Aβ42 containing amyloid plaques induced the neurofibrillary tangles and neurodegeneration. However, the connection between large amyloid plaques and AD is unlikely to be direct as the correlation between the extent of plaque formation and either the severity of dementia or the loss of neurons is poor. "
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    ABSTRACT: Alzheimer's (AD) is a progressive neurodegenerative disease that afflicts a significant fraction of older individuals. Although a proteolytic product of the Amyloid precursor protein, the Alphabeta42 polypeptide, has been directly implicated in the disease, the genes and biological pathways that are deployed during the process of Alphabeta42 induced neurodegeneration are not well understood and remain controversial. To identify genes and pathways that mediated Alphabeta42 induced neurodegeneration we took advantage of a Drosophila model for AD disease in which ectopically expressed human Alphabeta42 polypeptide induces cell death and tissue degeneration in the compound eye. One of the genes identified in our genetic screen is Toll (Tl). It encodes the receptor for the highly conserved Tl-->NFkB innate immunity/inflammatory pathway and is a fly homolog of the mammalian Interleukin-1 (Ilk-1) receptor. We found that Tl loss-of-function mutations dominantly suppress the neuropathological effects of the Alphabeta42 polypeptide while gain-of-function mutations that increase receptor activity dominantly enhance them. Furthermore, we present evidence demonstrating that Tl and key downstream components of the innate immunity/inflammatory pathway play a central role in mediating the neuropathological activities of Alphabeta42. We show that the deleterious effects of Alphabeta42 can be suppressed by genetic manipulations of the Tl-->NFkB pathway that downregulate signal transduction. Conversely, manipulations that upregulate signal transduction exacerbate the deleterious effects of Abeta42. Since postmortem studies have shown that the Ilk-1-->NFkB innate immunity pathway is substantially upregulated in the brains of AD patients, the demonstration that the Tl-->NFkB signaling actively promotes the process of Alphabeta42 induced cell death and tissue degeneration in flies points to possible therapeutic targets and strategies.
    PLoS ONE 12/2008; 3(12):e3966. DOI:10.1371/journal.pone.0003966 · 3.23 Impact Factor
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