PMC:3023298 / 71815-84278 JSONTXT

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disease (AD)\nAD is the most common cause of dementia occurring in middle and late life [226]. Population based surveys estimate that AD affects 7–10% of individuals \u003e65 years of age and possibly 50–60% of people over 85 years of age [227,228]. AD now affects about 2% of the population, or about 4 million people in the USA and ~35 million people worldwide [229]. The prevalence of AD is increasing proportionally to increased life expectancy and estimates predict that the prevalence will reach ~107 million by 2050 [230].\nMost cases of AD have unknown etiologies and are called sporadic and have a late onset; however, some cases, particularly those with early onset, are familial and are inherited as autosomal dominant disorders linked to mutations in the gene that encodes amyloid precursor protein (APP) [231,232,233,234] or genes that encode for presenilin proteins [235,236]. For late onset sporadic cases, a variety of risk factors have been identified in addition to old age [237]. The apolipoprotein E (ApoE) allele is a susceptibility locus with the ApoE4 type showing dose-dependent contributions [238]. Cardiovascular disease and head trauma are additional risk factors for AD [226].\nFigure 3 Brain atrophy and neurodegeneration in people with AD. Midsagittal views (center pictures) of the brains from an 85-year-old individual with AD and an 86-year-old normal control individual. The microscopic neuropathological hallmarks of AD are senile plaques (scale bar = 200 μm), neurofibrillary tangles (NFTs, scale bar = 50 μm.), and neuronal cell death determined by transferase-mediated biotin-dUTP nick-end labeling (TUNEL, brown nuclear staining, open arrows, scale bars = 10 μm) as seen in the hippocampus CA1 and in subcortical regions such as the thalamic lateral geniculate nucleus (LGN). The dementia in AD is caused by severe atrophy of the cerebral cortex, as indicated by the widening of the sulci and narrowing of the gyri (Figure 3) while normal aged individuals have broad gyri and narrow sulci (Figure 3). Neurons in the neocortex, hippocampus, basal forebrain, and brainstem (e.g., dorsal raphe) are selectively vulnerable in AD [239,240,241,242,243]. The numerous lesions that are formed in the brains of AD patients are called senile plaques, containing abnormal extracellular deposits of Aβ amyloid protein (Figure 3, arrows), and NFTs which are abnormal intracellular aggregates of protein containing hyperphosphorylated tau (Figure 3, arrows).\nIt is useful to view the neurodegeneration in AD in the context of neural systems and stages [244]. Surprisingly, the classification of the neurodegeneration in AD is still not clear [245]. Dying neurons are found in cortical and subcortical regions in the AD brain (Figure 3). By TUNEL, an in situ DNA fragmentation/damage assay, subsets of neocortical, hippocampal, and thalamic neurons in the AD brain can be found with double-stranded DNA breaks, suggesting that these cells are in the process of dying (Figure 3). This neuronal death has been interpreted as apoptosis [246,247,248]; however, this DNA damage is not specifically indicative of apoptosis [17,24,249]. Other reports conclude that apoptosis does not have a major role in the neuronal degeneration of AD [250]. Experiments on changes in the levels of proteins in the Bcl-2 family in AD postmortem brain are difficult to interpret, with studies showing up-regulation of both anti-apoptotic and pro-apoptotic proteins or no changes [247,251,252]. AD brain degeneration might involve caspase-3 activation as determined by the imunohistochemical detection of cleaved caspase-3 [249,251,253] and caspase gene expression [254]. Cleaved caspase-3 [253], caspase-9 [255] and caspase-6 [256] have been found in NFT-bearing neurons in AD. However other studies have not shown evidence for the accumulation of cleaved caspase-3 in neurons in the AD brain [257], but changes seen in early and late AD may differ [253]. It is also noteworthy that immunodetection of cleaved caspase-3 is not always equivalent to caspase-3 activation as determined biochemically [258]. Furthermore, caspase-3 functions in processes other than cell death, including neuronal differentiation, migration, and plasticity [259,260].\nNeuronal cell degeneration in AD occurs over a lengthy period. When considering the pathological classification of the primary neurodegeneration in AD it appears safe to conclude that based on morphology it is not classical apoptosis or necrosis. Autophagy could have a role in this neuronal cell death [249,261]. It might be more useful to consider neurofibrillary cell death separate from classical apoptosis and necrosis with some overlap in mechanisms according to the cell death matrix (Figure 2 and Figure 3). It could be important to know how neurons with neurofibrillary degeneration escape classical apoptosis and necrosis.\nThe mechanisms that cause the profound degeneration and loss of neurons in AD are not known, and existing information is incomplete. Abnormal processing or modification of APP and the cytoskeletal protein tau (a microtubule-associated protein) are involved in the pathogenesis (Figure 3) [262] resulting in amyloid (Aβ) deposits and neurofibrillary changes consisting of paired helical filaments, NFTs and dystrophic neurites (Figure 3) [262]. Cortical and hippocampal neuronal degeneration could be the consequence of a combination of several mechanisms including perturbations in protein metabolism, excitotoxicity, oxidative stress, mitochondrial perturbations, and inflammation. The possible specific mechanisms for neuronal degeneration in AD may involve dysfunction of NMDA receptors [264,265], dysregulation of Ca2+ and mitochondrial homeostasis [266,267], defects in synapses [268,269,270,271,272], abnormalities in the metabolism of APP and presenilin proteins, toxic actions of Aβ protein derived from APP [273,274], and cytoskeletal pathology [275,276].\nThere are possible disease links between intraneuronal Aβ and mitochondria suggesting an intracellular toxicity of Aβ [277,278,279]. Importantly, APP possesses a targeting sequence for mitochondria [277]. When over-expressed in cultured cells, APP interacts with mitochondrial import proteins, can arrest mitochondrial import, and can result in bioenergetic deficits [277]. In postmortem human brain samples, APP variants were found associated with mitochondria from the AD brain, but not mitochondria from control brain [278,280], and APP can interact with the translocase of the outer mitochondrial membrane (TOMM40) and TIMM23 [278]. The human AD autopsy brain shows evidence for mitochondrial impairments (for review see [267]). High mitochondrial APP levels mirror abnormalities in respiratory chain subunit levels and activity and enhanced ROS production [278]. Aβ can interact with the mitochondrial matrix protein Aβ-binding alcohol dehydrogenase in human AD brain and is believed to participate in mitochondrial dysfunction and oxidative stress [281]. A possible intraneuronal Aβ-mitochondria link was shown by EM in aged non-human primate neocortex [270].\nIn an APP transgenic (tg) mouse line (Tg2576) Aβ was also found to associate with mitochondria isolated from cerebral cortex [279]. It has also been reported that Aβ interacts with CyPD in mouse and human cerebral cortex mitochondria to potentiate synaptic stress [282]. Genetic deletion of CyPD (ppif) in human mutant APP tg mice (J-20 line) protects neurons from Aβ- and oxidative stress-induced cell death [282]. However, these abnormalities might not be related to the mPTP-driven cell death because these mice, and most other mouse models of AD, show scant or modest evidence for neurodegeneration resulting in neuronal cell death, despite tremendous brain burden of Aβ [283].\n\nMost Tg Mouse Models of AD are not Useful to Study Neuronal Cell Death\nAnimal experiments should provide critical insight into to the mechanisms of neurodegeneration in AD. However, most human APP and/or presenilin tg mice show substantial Aβ deposits in hippocampus and cortex, but do not develop robust neuronal loss [284,285,286]. Analysis of a different tg mouse line (APP23) showed that Aβ deposition is accompanied by a modest loss of CA1 neurons but no cortical neuron loss, despite an Aβ burden similar to that seen in CA1 [287]. None of these studies have found the formation of NFTs. Cleaved caspase-3 was not found in mutant APPSwedish tg mice [288], but sparse cleaved caspase-3-positive cells were found in mutant APP/presenilin mice [289]. Triple-tg mice harboring mutant presenilin, APP, and tau transgenes have intraneuronal accumulations of Aβ and phosphorylated tau, but neuronal loss was not reported [290]. However, in tg mice over-expressing Aβ protein, extracellular deposition Aβ and neuronal cell death is observed [291]. The neuronal cell death mechanism in these mice may involve p53 [291], consistent with cell culture findings that Aβ neurotoxicity involves p53 [292].\n\nCell Culture Models of Cortical and Hippocampal Neuron Cell Death and Interactions between APP, Aβ, Tau, and Caspases\nIt has long been thought by many researchers that Aβ is the primary cause of AD [272]. Extracellular application of Aβ can induce apoptosis [293] or necrosis [294] in cultured neurons. Extracellularly applied Aβ25–53 or Aβ1–40 induces mitochondrial dysfunction in primary cortical neurons [295], enhanced production of free radicals, intracellular Ca2+ destabilization, and DNA damage [296,297]. Studies of the specific intracellular signaling pathways that are activated by Aβ to trigger cell death are only now appearing in the literature. In studies of rodent neurons exposed to extracellular Aβ, the induction of apoptosis involves the Fas death receptor-Jun N-terminal kinase (JNK) pathway [298], the p75NTR-JNK pathway [299], and caspase-12 [300]. Neuronal cultures exposed to Aβ can be protected from neurotoxicity by caspase-8 inhibition and expression of dominant-negative Fas-associated protein with death domain (FADD), both components of the Fas death receptor pathway [301]. Some in vitro experiments have implicated p53 in neuron death trigged by extracellular Aβ [302,303], but other in vitro studies with Aβ-treated cortical neurons reveal a p53-independent mechanism for cell death involving the transcription factor E2F1 [304]. It is noteworthy that results of cell culture experiments using extracellular application of Aβ are likely to be dependent on Aβ concentration and oligomeric state. When human neuron primary cultures are treated with Aβ at concentrations closer to physiological levels for up to 3 days, evidence for apoptosis is scarce; however, Bcl-2 levels are down-regulated and Bax levels are up-regulated [305]. Thus, extracellular Aβ at physiological concentrations might render neurons more sensitive to cell stress rather than kill them outright. Intracellular Aβ1-42 exposure (as little as 1 picomolar) is, in contrast, toxic to human cortical neurons, and this toxicity requires de novo protein synthesis, Bax, p53, and caspases, suggesting cell death by some form of apoptosis [292].\nExperiments have been performed to link APP and presenilins to cell death. Over-expression and intracellular accumulation of APP activates caspase-3 [306]. APP is a target of caspase-3 [306] and caspase-6 [307], and APP cleavage by caspase-3 or caspase-6 may promote Aβ formation [307,308]. Thus, increased production of Aβ may be a consequence of neuronal apoptosis. Recent work has shown that shedded N-terminal fragments of APP are surface ligands that bind death receptor 6 (DR6) to trigger axon pruning through caspase-6 and neuron death through caspase-3 [309]. Neurotrophin deprivation engages the shedding of APP to activate DR6 [309]. Presenilin proteins can influence mitochondrial regulation of apoptosis, such as Bax activation and cytochrome c release, through interactions with Bcl-XL [310], and they are also substrates for caspase-3 [311]. However, over-expression of human wild-type or mutant presenilin-1 or presenilin-2 does not enhance apoptosis in neurons [312,313]. Other work indicates that the presenilin-1 mutation sensitizes neurons to DNA damage-induced apoptosis [314]. More cell culture work needs to be done on the basic mechanisms of human neuron degeneration and on APP and Aβ neurotoxicity mechanisms under basal conditions and in the presence of familial AD-related and tau gene mutations."}