Alzheimer's disease is a neurodegenerative disorder characterized by a progressive loss of memory, intellectual function, and cognitive abilities (Wisniewski et al., 1994). In the normal population, AD usually arises during the fifth or later decades of life and affects approximately 10% of individuals aged 65 and above (Keefover, 1996). In DS, however, almost 100% of patients develop Alzheimer's-type neuronal pathology by the third to fourth decade of life (Dalton and Wisniewski, 1990). There is now considerable evidence that both amyloid ^-peptide (A/3) and oxidative stress are implicated in the pathogenesis of AD (Friedlich and Butcher, 1994; Mattson, 1997a). It has been shown that A/3, which is a normal product of cell metabolism derived from the /3-amyloid precursor protein (APP), is overproduced in the brain of individuals with AD and forms insoluble fibrillar aggregates, called "senile" or "neuritic" plaques, that promote neuronal degeneration (Mattson, 1997b). This neurotoxic effect of A/3 deposits may involve the generation of ROS, which disrupts cellular calcium homeostasis and renders neurons more susceptible to excitotoxicity and apoptosis (Behl et al., 1994, Behl, 1997). Three genes have been identified that, when mutated, lead to aberrant APP processing and increased levels of A/3: APP, presenilin 1 (PS1), and presenilin 2 (PS2) (Lendon et al., 1997). Mutations in APP cause a shift in APP processing, leading to a decreased production of the secreted neuroprotective form of APP and an increased liberation of A/3 (Mattson, 1997b). Mutations in presenilin genes may lead to increased generation of A/3 by disrupting the calcium homeostasis of the endoplasmic reticulum, which results in mitochondrial impairment, increased oxidative stress, and consequently aberrant APP processing (Guo et al., 1997). In addition, the s4 allele of the apolipoprotein E gene has been shown to increase the risk of AD, and some data suggest that this could occur via a perturbation in the level of oxidative stress in the brain parenchyma and vasculature and a stimulation of A/3 fibril formation (Mattson, 1997a).
Individuals with DS have three copies of both APP and SOD1 genes (the gene coding for APP is also localized on chromosome 21). Therefore, individuals with DS might be exposed, from the beginning of life, to a concomitant excess of free radicals and APP levels. It is believed that the prooxidant conditions, together with enhanced APP formation, may be responsible for the early and invariable /3-amyloid accumulation in these patients. This hypothesis is supported by several lines of evidence. Ceballos et al. (1991) have demonstrated that SOD1 is expressed predominantly in the pyramidal neurons of the brain, which are the neurons that degeneate in AD. The elevated levels of SOD1 in DS might therefore perturb the ROS balance in these neurons, leading to oxidative damage and aberrant APP processing. In addition, Busciglio and Yankner (1995) reported clear evidence that oxidative stress and neuronal damage begin accumulating in utero in the DS brain: cortical neurons from aborted DS conceptuses show increased lipid peroxidation and apoptosis in culture as compared with normal cortical neurons. This effect seems to be mediated via excess levels of hydrogen peroxide as it can be prevented with compounds such as N-acetylcysteine and catalase (but not by SOD1). These data indicate that a defect in the metabolism of ROS exists in neurons of DS fetuses that places the developing brain in an environment of increased oxidative stress. This increased oxidative stress might cause aberrant APP processing, leading to early cerebral A/3 deposits. Furthermore, Bar-Peled et al. (1996) demonstrated that SOD1 overexpression in SOD1 transgenic mice leads to a chronic prooxidant state in the brain, as manifest by increased levels of oxidized glutathione and altered calcium homeostasis. This chronic oxidant state renders neurons more susceptible to apoptotic death when subjected to kainic acid and may also render neurons more susceptible to /3-amyloid toxicity. Moreover, we also demonstrated, using GPX1 knockout mice, that an imbalance in the SOD1 to GPX1 ratio in the brain leads to increased susceptibility of neurons to H202-mediated toxicity (de Haan/Bladier et al., 1998). Interestingly, it has been shown that the promoter of the APP gene contains a heat shock element (HSE) (Salbaum et al., 1988; Dewjii and Do, 1996) and that oxidative stress can activate gene transcription via the HSE (Liu and Thiele, 1996). This would suggest the following scenario: oxidative stress, due to the elevated SOD1/GPX ratio, leads to higher levels of APP via the transcriptional induction of the APP gene. This is turn causes an increased formation of A/8 (due to aberrant APP processing) and fibrillar amyloid deposits that result in further oxidative stress, disruption of calcium homeostasis, mitochondrial dysfunction, and consequently increased apop-tosis and neurodegeneration (Fig. 4).
Finally, further evidence that oxidative stress, together with excess APP, may be involved in the early onset of AD in patients with DS comes from the fact that elevated levels of APP are insufficient to produce amyloid deposition by the age at which it occurs in DS. Stably transfected cells overexpressing APP exhibit increased levels of A/3 but do not produce any
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Figure 4 A possible role for SOD1 and APP in the early onset of Alzheimer's disease in patients with DS. Elevated levels of SODl/(GPXs+catalase) ratio in the brain of patients with DS causes oxidative stress, which, in conjunction with elevated APP levels, leads to an alternative APP processing; this results in decreased production of the neuroprotective form of APP and increased liberation of toxic A/3. In addition, oxidative stress further increases APP levels through the induction of APP transcription via a heat shock element (HSE) in the promoter of the APP gene. This leads to the elevated formation of A/3 and amyloid plaques, which, in turn, cause further oxidative stress, mitochondrial dysfunction, disruption of calcium homeostasis, and increased apoptosis and neurodegeneration. Increased amyloid deposition, together with apoptosis and neurodegeneration in the brain, may contribute to the early onset of AD-type pathology in DS.
extracellular A/3 deposits (Maruyama et al., 1990), and mice overexpressing APP do not completely develop the features of AD as they do not display extracellular deposits of fibrillar A/3 and/or neuronal degeneration (Mattson, 1997b). Nevertheless, data support the notion that the trisomy of APP may be necessary for the development of AD dementia in patients with DS. Indeed a case has been reported of a 78-year-old woman with DS but no Alzheimer's disease—trisomy 21 was partial and the gene for APP was present in only two copies (Prasher et al., 1998). Therefore these data indicate that other factors, such as oxidative stress (in conjunction with high APP levels), are needed to exacerbate /3-amyloidosis and lead to the early onset of AD seen in DS. Further experiments using transgenic mouse models are needed to confirm these hypotheses. The generation of mice overexpressing both APP and SOD1 genes, for example, should provide a good model system in which to test the notion that a synergistic interaction of APP and SOD1 predispose patients with DS to the pathogenesis of AD.
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