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The amyloidhypothesis ofAlzheimer's diseaseat 25 years Dennis J. SelkoeJohn Hardy2016 год

The amyloid hypothesis of Alzheimer's disease at 25 years
review

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Аннотация: Review29 March 2016Open Access The amyloid hypothesis of Alzheimer's disease at 25 years Dennis J Selkoe Dennis J Selkoe Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA Search for more papers by this author John Hardy Corresponding Author John Hardy Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK Search for more papers by this author Dennis J Selkoe Dennis J Selkoe Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA Search for more papers by this author John Hardy Corresponding Author John Hardy Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK Search for more papers by this author Author Information Dennis J Selkoe1,‡ and John Hardy 2,‡ 1Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA 2Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK ‡These authors contributed equally to this work *Corresponding author. Tel: +44 203 108 7466; E-mail: [email protected] EMBO Mol Med (2016)8:595-608https://doi.org/10.15252/emmm.201606210 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild-type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long-term potentiation, and enhance long-term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD-relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau-positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target. Glossary Microgliosis early non-specific proliferation and migration of microglial cells, macrophage-like cells in the central nervous system, as the first response to brain damage. Astrocytosis final response to brain damage and injury with proliferation of astrocytes, a type of glial cell responsible for maintaining extracellular ion and neurotransmitter concentrations, modulating synapse function, and forming the blood–brain barrier. Neurofibrillary tangles accumulation of hyperphosphorylated tau protein, commonly found in Alzheimer's disease, that aggregates inside nerve cell bodies, also known as dystrophic neurites. Plaque deposition aggregates of amyloid fibrils that are deposited outside neurons in dense formations, also known as senile plaques or neuritic plaques. FAD familial AD caused by inherited mutations in APP and presenilin (typically early-onset) by opposition to "sporadic" or late-onset AD Introduction Few problems in modern biomedicine have garnered as much scientific interest and public concern as has Alzheimer's disease. Virtually unknown to the general public four decades ago, AD has risen in prevalence to an estimated 40 million patients worldwide. The true number must be much higher, given the increasing recognition that the disease begins in the brain at least 2–3 decades before one first forgets the name of a grandchild or where one has parked one's car. Since molecular studies of AD began in earnest in the early 1980s, thousands of scientists and healthcare professionals have delved into all aspects of this complex, multifactorial syndrome, hoping to help patients now and prevent others from developing it in the future. Although the progressive buildup of amyloids of diverse protein composition in various systemic organs has been known to cause devastating diseases for more than a century, the idea put forward by George Glenner (Glenner & Wong, 1984) that the particular amyloidogenic protein accumulating in AD (Aβ) could be causative has met with considerable skepticism over the ensuing years. Precisely why this idea has been so controversial is not clear (Selkoe, 2011), but the steady accrual of data from many preclinical and clinical studies has increasingly supported it. The amyloid (or Aβ) hypothesis (Beyreuther & Masters, 1991; Hardy & Allsop, 1991; Selkoe, 1991; Hardy & Higgins, 1992) has become the dominant model of AD pathogenesis and is guiding the development of potential treatments. We reviewed the evidence for this hypothesis (Fig 1) a dozen years ago (Hardy & Selkoe, 2002). Space precludes a full examination here of the enormous literature on Aβ since that review; a monograph on AD pathobiology contains many details (Selkoe et al, 2012). But in the context of continuing concern about the concept and yet the recent emergence of apparently positive clinical trial data, a critical analysis of the latest developments in laboratory and clinic is warranted and timely. We review here numerous new developments since our prior review of this hypothesis, on which ever-increasing scientific effort is being expended. We also summarize the salient findings over three decades that undergird the amyloid hypothesis (Box 1), and we discuss several alternative concepts or concerns that have been counterposed to it (Table 1). Box 1: Evidence supporting a key role for Aβ dyshomeostasis in initiating AD All AD patients undergo progressive Aβ deposition followed by surrounding neuritic and glial cytopathology in brain regions serving memory and cognition. Mutations within and immediately flanking the Aβ region of APP cause aggressive forms of FAD. Humans with trisomy 21 (Down's syndrome) harbor 3 copies of APP and invariably develop neuropathologically typical AD. Those who die in their early-to-mid teens (from other causes) show abundant diffuse Aβ plaques without neuritic dystrophy, microgliosis, astrocytosis, and tangle formation, all of which accrue gradually in such subjects in the late teens and beyond. Inheritance of a missense mutation in APP that decreases the production and aggregation of Aβ lifelong protects against AD and age-related cognitive decline. Missense mutations in presenilin 1 or 2 are the most common cause of early-onset AD, and presenilin is the catalytic subunit of γ-secretase. The mutations result in relative increases in the production of Aβ42/43 peptides. These hydrophobic species self-aggregate, leading to profound Aβ deposition in mid-life. ApoE4 carriers were once included in typical late-onset AD. This allele was found to markedly increase AD risk and decrease brain clearance of Aβ, leading to excess Aβ aggregation and typical downstream AD neuropathology. Aβ42 oligomers isolated from typical (late-onset) AD brains decrease synapse density, inhibit LTP, and enhance long-term synaptic depression in rodent hippocampus, and their intraventricular injection impairs memory in healthy adult rats. Human Aβ42 oligomers induce tau hyperphosphorylation at AD-relevant epitopes and cause neuritic dystrophy in cultured rat neurons; co-administering Aβ antibodies fully prevents this. Aβ oligomers occur in a penumbra around many neuritic plaques. Accordingly, synapse decreases occur in a centrifugal gradient: less abnormality at longer distances from the plaque edge. Based on many human biomarker studies, low CSF Aβ42 and positive amyloid-PET scans precede other AD-related changes (increased CSF tau, decreased cerebral glucose metabolism, brain atrophy, clinical dementia) by years. Trials of 3 different Aβ monoclonal antibodies (solanezumab, crenezumab, and aducanumab) have suggested slowing of cognitive decline in post hoc analyses of mild (but not moderate) AD patients. Other amyloidogenic proteins have been proven to cause progressive human organ failure, and therapeutic lowering of the amyloid or its precursor protein yields therapeutic benefits in patients. Figure 1. The sequence of major pathogenic events leading to AD proposed by the amyloid cascade hypothesisThe curved blue arrow indicates that Aβ oligomers may directly injure the synapses and neurites of brain neurons, in addition to activating microglia and astrocytes. Download figure Download PowerPoint Table 1. Findings that appear to undercut the amyloid hypothesis of AD and counterarguments that could explain these discrepancies Findings Counterarguments Amyloid plaque burden correlates much less well with degree of cognitive impairment than do neurofibrillary tangle counts Aβ deposits appear to be a very early and widespread event that is distant to the clinical dementia and can lead to many downstream cellular and molecular changes (e.g., microgliosis, neuritic dystrophy, tangles, etc.) that are more proximate to and causative of neuronal dysfunction Many humans show sometimes abundant Aβ deposits at death but were not noticeably demented Some or many of these deposits are diffuse plaques (not rich in abnormal neurites and glia); the patients were often not tested rigorously before death; and Aβ oligomer levels per plaque are much lower than in AD brains (Esparza et al, 2013), suggesting that plaques can effectively sequester oligomers in a non-diffusible, less neurotoxic state, at least up to a point Some human neuropathological studies suggest tangles may precede amyloid plaques Such studies may not have searched systematically for diffuse plaques or soluble Aβ oligomers in the brain. Human genetics proves that Aβ-elevating APP mutations lead to downstream alteration and aggregation of wild-type tau, whereas tau mutations do not lead to Aβ deposition and amyloid-related dementia A hypothesis that AD is fundamentally due to loss of presenilin function has been put forward AD-causing presenilin mutations may indeed act through partial loss of function of this protease, but these heterozygous mutations do not produce clinically detectable loss of presenilin function (e.g., Notch phenotypes), and organismal development and function are normal until the carriers develop typical AD symptoms in mid-life, heralded by elevated Aβ42/43 to Aβ40 ratios. Moreover, 99.9% of all AD patients have wild-type presenilins Numerous clinical trials of anti-amyloid agents have not met their pre-specified endpoints Several of these agents had inadequate preclinical data, poor brain penetration, little human biomarker change, and/or low therapeutic indexes (e.g., tramiprosate; R-flurbiprofen; semagacestat). Most such failed trials enrolled many patients in the late-mild and moderate stages of AD, whereas other trials conducted in very mild or mild AD produced suggestive evidence of clinical benefit. AD trials done prior to obligatory amyloid-PET imaging turned out to have up to ~25% of subjects that were amyloid-negative (i.e., did not have AD) New insights from AD genetics and APP homeostasis The fact that AD-causing mutations in APP and in presenilins 1 and 2 alter APP proteolytic processing in a way that elevates the relative levels of the Aβ42 or Aβ43 peptides has long been known (Scheuner et al, 1996; NB: Those mutations in APP that lie within the Aβ sequence increase the self-aggregation of the resultant peptides, not their production). A key mechanistic explanation was the discovery that the presenilin genes encode the active site of the intramembrane-cleaving γ-secretase enzyme (De Strooper et al, 1998; Wolfe et al, 1999). Subsequent studies have begun to illuminate how presenilin mediates intramembrane proteolysis (Qi-Takahara et al, 2005; Takami et al, 2009; Chavez-Gutierrez et al, 2012; Okochi et al, 2013; Fernandez et al, 2014): an initial endopeptidase cleavage of APP near the transmembrane/cytoplasmic interface of APP (the ε-cleavage) is followed by multiple carboxypeptidase cleavages that each sequentially removes 3 or 4 C-terminal amino acids (i.e., approximately one turn of the intramembrane helix) (Fig 2). This process yields two product lines that start with either the Aβ48/49 or the Aβ49/50 ε-cleavage. Although the precise molecular effects of different presenilin mutations differ somewhat, in all cases the mutations appear to decrease this C- to N-terminal cleavage "processivity" and thus increase the relative production of longer (more hydrophobic and self-aggregating) Aβ peptides. This elegant model provides a biochemical explanation for earlier work showing that pathogenic presenilin mutations often increase the Aβ42/Aβ40 ratio in humans. γ-Secretase reactions conducted directly in presenilin-mutant AD brain tissue showed that all presenilin mutations studied decreased this carboxypeptidase-like activity, and assays in a few "sporadic" AD brains suggested that a similar decrease in processivity might occur in some non-presenilin-mutant cases (Szaruga et al, 2015). Aβ42, Aβ43, and longer Aβ peptides are highly self-aggregating, whereas Aβ40 may actually be anti-amyloidogenic (Kim et al, 2007). Figure 2. Progressive cleavages of the APP transmembrane domain by the Presenilin/γ-secretase complex Download figure Download PowerPoint One group has emphasized that the aforementioned mechanism represents a loss of function of presenilin and have proposed that the neural phenotype of AD patients is fundamentally due to a loss of presenilin function, independent of effects on Aβ production (Shen & Kelleher, 2007; Xia et al, 2015). They have studied presenilin-1 mutations that generally lower Aβ and hardly raise relative Aβ42 levels, but this work may overlook an elevation of the Aβ43 and other longer species, which are highly amyloidogenic (Saito et al, 2011). Although AD-causing presenilin mutations can indeed be interpreted as partial loss of function from a genetics perspective, pinpointing the function of presenilin as an aspartyl endopeptidase allows one instead to speak in biochemical terms of a functional shift of the principal proteolytic cleavages to more C-terminal bonds in the substrate (Kretner et al, 2016). Humans with pathogenic presenilin mutations are heterozygotes and experience no loss of function of Notch cleavage; rather, they have accelerated Aβ42 and Aβ43 accumulation that long precedes their AD-typical memory syndrome. Most importantly, > 99% of all AD patients (including all other forms of familial disease) express wild-type presenilin, so loss of presenilin function cannot be a general mechanism of AD pathogenesis. The original formulation of the amyloid hypothesis was based in part on the discovery that the APP gene is on chromosome 21, implying that individuals with Down's syndrome develop typical Alzheimer neuropathology because they produce too much Aβ lifelong. This supposition has been substantiated by the identification of humans with different segmental microduplications of sub-regions of chromosome 21. Rare individuals with translocation Down's syndrome involving only the distal part of chromosome 21 telomeric to the APP gene have Down's features but do not get AD (Prasher et al, 1998). Conversely, those rare individuals who have the APP gene micro-duplicated but not the rest of the chromosome do not have Down's syndrome but get AD, typically in their mid-50s (Rovelet-Lecrux et al, 2006). These findings show conclusively that lifelong overexpression of wild-type APP causes AD. Even more remarkable has been the identification of an APP missense mutation (A673T) at the second amino acid of the Aβ region that results in a lifelong decrease in APP cleavage by β-secretase (Jonsson et al, 2012). Moreover, this benefit may be compounded, because the mutant Aβ peptide that is generated has altered aggregation properties (Benilova et al, 2014; Maloney et al, 2014; Zheng et al, 2015). A673T carriers have a lower risk of clinical AD and even of age-related cognitive decline without clinical AD (Jonsson et al, 2012), and they may not show plaque deposition at age 100 (Kero et al, 2013). The reduced amyloid deposition resulting from this AD-protective mutation strongly supports the amyloid hypothesis. Improved modeling of the amyloid hypothesis in rodent and cellular systems Concern has been expressed about the limitations of available rodent and cellular models of β-amyloid pathogenicity (Table 2). Early APP mouse models (e.g. Games et al, 1995; Hsiao et al, 1996) suffered from reliance on high transgene expression to drive plaque deposition and from a lack of tangle cytopathology and neuronal death. Crossing FAD-mutant APP mice with mutant MAPT (tau) transgenic (tg) mice succeeded in augmenting tau pathology and suggested that tangle-like changes occur downstream of Aβ accumulation, but this involved transgene overexpression and multiple AD mutations (Lewis et al, 2001). Recently, mice with gradual Aβ plaque accrual have been developed by the judicious use of selective knockin of human mutations into endogenous mouse APP without overexpression (Saito et al, 2014). Moreover, stem cell-derived human neurons cultured from skin biopsies of FAD subjects have been used to show first Aβ accumulation and then tau alteration in the absence of overexpression (Shi et al, 2012; Choi et al, 2014; Muratore et al, 2014; Moore et al, 2015) suggesting that the lack of tangle formation in early mouse models was related to the absence of human tau. This progress means we are now able to model a substantial part of the amyloid cascade in culture. In both cellular and mouse models, extensive data now suggest that the neurotoxicity of Aβ is in considerable part dependent on expression of human tau (Rapoport et al, 2002; Jin et al, 2011; Roberson et al, 2011). Table 2. Toward a more complete modeling of the pathogenesis of AD amyloid Year System Achievement Critique References 1995 APP transgenic mouse Plaque Pathology Overexpression, no downstream pathology Games et al (1995) 2000 MAPT mutant transgenic mouse Tangle Pathology Overexpression: no plaque pathology Lewis et al (2000) 2001 APP X MAPT transgenic mice Plaque and tangle pathology Overexpression of both transgenes: artificiality of two mutations Lewis et al (2001) 2012 Down's syndrome derived stem cell neurons Diffuse plaque pathology: evidence for pre-tangles Not full pathology Shi et al (2012) 2014 Complex APP mutation knockin into mouse genome Plaque pathology without overexpression Artificiality of multiple mutations: no downstream pathology Saito et al (2014) 2014 Overexpression of APP mutations in human neuronal lines in gel system Convincing plaque pathology and also tangle pathology Overexpression Choi et al (2014) 2015 APP and PSEN mutant stem cell lines Diffuse plaque pathology and tau pathology Moore et al (2015) Cell biology of new AD risk genes Although the importance of ApoE4 as the major risk factor for AD was discovered in 1993 (Corder et al, 1993), it is only since the advent of genomewide association studies and, more recently, exome and genome sequencing that other risk loci for late-onset disease have been discovered. Whereas the recently described loci are usually much weaker in effect (Lambert et al, 2013) or much rarer (Guerreiro et al, 2013; Jonsson et al, 2013) than ApoE4, they have helped delineate additional biological processes in AD pathogenesis. Three types of processes have emerged as especially important: cholesterol/sterol metabolism; inflammation and the brain's innate immune system; and endosomal vesicle recycling (Jones et al, 2010). Apolipoprotein E and other components of cholesterol/sterol metabolism A role for cholesterol in AD has long been suspected, based on the genetic implication of ApoE in the disease as well as the contrasting effects of cholesterol loading or depletion on amyloid pathology in APP tg mice (Refolo et al, 2000, 2001). Work in APP mice expressing different human ApoE alleles has shown that a major pathogenic influence of ApoE involves differential isoform effects on the clearance of Aβ (Castellano et al 2011: discussed below). The ABCA7 lipid transporter has also been identified as a genetic locus for the disease (Hollingworth et al, 2011), and loss-of-function mutations increase AD risk about threefold (Steinberg et al, 2015). ABCA7 is expressed in neurons, microglia, and peripheral macrophages, and it normally promotes the efflux of lipids from cells to apolipoproteins and also regulates phagocytosis. Crossing ABCA7 knockout mice to mutant hAPP mice caused a doubling of insoluble Aβ levels and amyloid plaques without changing APP processing, suggesting that like ApoE, ABCA7 is involved in Aβ clearance (Kim et al, 2013). However, the biochemical details through which both ApoE and ABCA7 influence the development of Aβ pathology need to be pinpointed. The innate immune system in Alzheimer's disease Neuropathologists have long suggested that the brain's innate immune system, including the microglial response to plaque formation, was an important factor in AD pathogenesis. For example, the early observation of multiple elements of the classical complement cascade in and around neuritic plaques (McGeer et al, 1989) was prescient. In the last few years, genetic variability in that system has emerged as a compelling determinant of AD risk, implicating many components of innate immunity and the complement cascade as risk factors in the disease (Jones et al, 2010). Three such risk genes have been investigated in some detail: Complement Receptor 1 (CR1; Lambert et al, 2009), CD33 (Bertram et al, 2008), and TREM2, and all three appear to be involved either directly or indirectly in the response of microglia to Aβ deposition. Blockade of CR1 inhibits microglial activation and potentiates microglial phagocytosis (Crehan et al, 2013). Inactivation of CD33 in primary microglia also potentiates microglial uptake of Aβ (Griciuc et al, 2013), and TREM2 is responsible for sustaining microglial phagocytosis of Aβ (Wang et al, 2015). Thus, all three genetically implicated microglial proteins may be involved in helping to maintain the AD microglial phenotype of phagocytosing Aβ deposits. Accordingly, these 3 genes undergo increased expression during plaque development (Griciuc et al 2013, Wang et al, 2015; Matarin et al, 2015) and CSF TREM2 levels go up as plaque load increases, suggesting it may be a useful biomarker (Suárez-Calvet et al, 2016). TREM2 is emerging as a key molecular determinant of the CNS response to Aβ accumulation (Forabosco et al, 2013; Zhang et al, 2013; Matarin et al, 2015). However, the biology of TREM2, a Type 1 single-transmembrane receptor which is principally but not exclusively expressed in microglia and undergoes ADAM/γ-secretase processing (Wunderlich et al, 2013; Kleinberger et al, 2014), is incompletely understood [reviewed in (Lue et al, 2015)]. The most studied mutation, R47H, may increase the risk of AD to the same extent that ApoE4 does although it is much rarer (Guerreiro et al, 2013; Jonsson et al, 2013). The upregulation of TREM2 in a subset of microglia in amyloid plaques of hAPP tg mice (e.g., Guerreiro et al, 2013) suggests that the known function of TREM2 in phagocytosis is compromised during plaque development. A current hypothesis is that R47H and other AD-associated TREM2 mutations confer loss of function in microglia. Deleting one TREM2 allele in hAPP tg mice significantly decreased the number of microglia associated with Aβ deposits (Ulrich et al, 2014). Conversely, TREM2 overexpression in hAPP tg mice decreased amyloid plaque burden, neuroinflammation, synapse loss, and spatial memory deficits (Jiang et al, 2014). And TREM2 mutations can alter its transport to the cell surface and shedding, associated with impaired phagocytic function (Kleinberger et al, 2014). The latter work has led to evidence that levels of the shed ectodomain in extracellular fluid and CSF are lower in AD cases associated with TREM2 mutations. Endosomal vesicle recycling in Alzheimer's disease The final set of recently identified loci for late-onset AD map to processes regulating endosomal vesicle recycling (Jones et al, 2010). This category includes SORL1, BIN1, and PICALM (Rogaeva et al, 2007; Lambert et al, 2013; Zhao et al, 2015). SORL1 had previously been shown to be directly involved in the processing of APP (Andersen et al, 2005), and work in human stem cell-derived neurons carrying the SORL1 risk haplotype confirmed this association (Young et al, 2015). Likewise, PICALM appears to be involved directly in endosomal APP processing (Kanatsu et al, 2014). In addition, PICALM has been implicated in the transport of brain Aβ across the blood–brain barrier: induced pluripotent stem cell (iPSC)-derived human endothelial cells carrying an AD-protective allele exhibited higher PICALM levels and enhanced Aβ clearance (Zhao et al, 2015). In summary, mechanistic studies linking several of the recently identified risk genes for late-onset (previously "sporadic") AD to aspects of Aβ homeostasis provide new support for the amyloid hypothesis as a driving factor in AD pathogenesis. They also suggest new avenues for therapeutic intervention, such as intervening in brain cholesterol metabolism and modulating the response of the innate immune system to amyloid deposition. Recent findings help resolve controversies about the role of Aβ Connecting plaques and tangles: Aβ can drive tau alteration The temporal sequence of the two canonical lesions Alois Alzheimer noted in his 1906 index case has been debated ever since. An elegant histopathological staging system created by Braak and Braak (1991) is now widely used to establish the severity of AD neuropathology. This scale principally described the progression of AD-type cytoskeletal changes, that is, neurofibrillary tangles and dystrophic neurites, in unrelated humans of increasing age (it could not yet include assays for accrual of oligomeric forms of Aβ). The detection of modest amounts of neurofibrillary change in limbic regions of young or middle-aged individuals dying of other causes does not imply that such individuals would necessarily have developed AD had they lived longer. Instead, human genetic and biomarker studies have provided the answer to the sequence of Aβ and tau accumulation in AD. Inherited mutations in APP and presenilin (i.e., in the substrate and the protease for Aβ generation) cause early-onset Aβ deposition (Lemere et al, 1996a,b; Bateman et al, 2012) followed by accumulation of tangles/neurites containing filaments of wild-type tau, so amyloid can clearly precede tangles in humans. In contrast, mutations in the tau gene lead to a form of frontotemporal dementia without subsequent accrual of Aβ. Thus, Aβ accumulation can lead to progressive tau deposition, but the converse has not been clearly demonstrated in humans. Laboratory studies support this sequence. Crossing hAPP tg mice with hTau tg mice significantly enhances tau deposition without changing Aβ deposition (Lewis et al, 2001). Crossing an APP tg mouse to a tau knockout mouse leads to substantially less behavioral deficits in the offspring than when tau is expressed (Roberson et al, 2011). Treating normal rat neurons in culture with soluble Aβ oligomers isolated from AD cortex causes neuritic dystrophy and AD-type tau hyperphosphorylation, but no dystrophy ensues if tau is first knocked down (Jin et al, 2011). Several similar studies suggest that Aβ—particularly soluble oligomers of Aβ42 (Shankar et al, 2008)—can trigger AD-type tau alterations, supporting the sequence that human genetics has indicated. The expression of human tau seems to be "permissive", enabling certain downstream neuronal consequences of progressive Aβ accrual to occur (Maruyama et al, 2013). How ApoE4 promotes AD: chronically decreased Aß clearance Humans expressing the ApoE4 protein develop more plaque and vascular β-amyloid deposits than those expressing only ApoE3 (Rebeck et al, 1993), and this has been confirmed in genetically engineered mice (Holtzman et al, 2000). A detailed quantitative study of Aβ homeostasis using in vivo microdialysis in hAPP × hApoE crossed mice has shown that Aβ clearance (but not Aβ production) is decreased by ApoE4 > E3 > E2, closely paralleling the degree of Aβ deposition in such mice (Castellano et al, 2011). The decrease in clearance of soluble Aβ was observed in young mice well before any amyloid deposition. The results strongly suggest that ApoE contributes to AD risk at least in part by differentially regulating sol
Год издания: 2016
Авторы: Dennis J. Selkoe, John Hardy
Издательство: Springer Nature
Источник: EMBO Molecular Medicine
Ключевые слова: Alzheimer's disease research and treatments, Tryptophan and brain disorders, Dementia and Cognitive Impairment Research
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