2017年阿尔茨海默病十大研究进展

第一位：增强线粒体蛋白质质控降低Aβ神经毒性

Nature. 2017 Dec 14;552(7684):187-193. Enhancingmitochondrial proteostasis reduces amyloid-β proteotoxicity.

Abstract

Alzheimer's disease is a common and devastating diseasecharacterized by aggregation of the amyloid-β peptide. However, we knowrelatively little about the underlying molecular mechanisms or how to treatpatients with Alzheimer's disease. Here we provide bioinformatic andexperimental evidence of a conserved mitochondrial stress response signaturepresent in diseases involving amyloid-β proteotoxicity in human, mouse andCaenorhabditis elegans that involves the mitochondrial unfolded proteinresponse and mitophagy pathways. Using a worm model of amyloid-βproteotoxicity, GMC101, we recapitulated mitochondrial features and confirmedthat the induction of this mitochondrial stress response was essential for themaintenance of mitochondrial proteostasis and health. Notably, increasingmitochondrial proteostasis by pharmacologically and genetically targetingmitochondrial translation and mitophagy increases the fitness and lifespan ofGMC101 worms and reduces amyloid aggregation in cells, worms and in transgenicmouse models of Alzheimer's disease. Our data support the relevance ofenhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases,such as Alzheimer's disease.

第二位：研究发现了一种新的小胶质细胞类型可以限制AD的发展

Cell. 2017 Jun 15;169(7):1276-1290.e17. A UniqueMicroglia Type Associated with Restricting Development of Alzheimer'sDisease.

Abstract

Alzheimer's disease (AD) is a detrimentalneurodegenerative disease with no effective treatments. Due tocellular heterogeneity, defining the roles of immune cell subsets inAD onset and progression has been challenging. Using transcriptional single-cell sorting,we comprehensively map all immune populations in wild-type and AD-transgenic(Tg-AD) mouse brains. We describe a novel microglia type associated withneurodegenerative diseases (DAM) and identify markers, spatial localization,and pathways associated with these cells. Immunohistochemical staining of miceand human brain slices shows DAM with intracellular/phagocytic Aβ particles.Single-cellanalysis of DAM in Tg-AD and triggering receptor expressed onmyeloid cells 2 (Trem2)^-/- Tg-AD reveals that the DAM programis activated in a two-step process. Activation is initiated in aTrem2-independent manner that involves downregulation of microglia checkpoints,followed by activation of a Trem2-dependent program. This unique microglia-typehas the potential to restrict neurodegeneration, which may have importantimplications for future treatment of AD and other neurodegenerative diseases.

第三位：研究发现ApoE各等位基因对APP的转录和Aβ分泌具有不同的作用

Cell. 2017 Jan 26;168(3):427-441.e21. ApoE2, ApoE3,and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion.

Abstract

Human apolipoprotein E (ApoE) apolipoprotein is primarilyexpressed in three isoforms (ApoE2, ApoE3, and ApoE4) that differ only by tworesidues. ApoE4 constitutes the most important genetic risk factor for Alzheimer'sdisease (AD), ApoE3 is neutral, and ApoE2 is protective. How ApoE isoformsinfluence AD pathogenesis, however, remains unclear. Using ES-cell-derivedhuman neurons, we show that ApoE secreted by glia stimulates neuronal Aβproduction with an ApoE4 > ApoE3 > ApoE2 potency rank order. Wedemonstrate that ApoE binding to ApoE receptors activates dual leucine-zipperkinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2MAP kinases. Activated ERK1/2 induces cFos phosphorylation, stimulating thetranscription factor AP-1, which in turn enhances transcription of amyloid-βprecursor protein (APP) and thereby increases amyloid-β levels. This molecularmechanism also regulates APP transcription in mice in vivo. Our datadescribe a novel signal transduction pathway in neurons whereby ApoE activatesa non-canonical MAP kinase cascade that enhances APP transcription andamyloid-β synthesis.

第四位：研究发现ApoE4显著增强tau蛋白介导的神经变性

Nature. 2017 Sep 28;549(7673):523-527. ApoE4 markedlyexacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.

Abstract

APOE4 is the strongest genetic risk factor for late-onset Alzheimerdisease. ApoE4 increases brain amyloid-β pathology relative to other ApoEisoforms. However, whether APOE independently influences tau pathology, theother major proteinopathy of Alzheimer disease and other tauopathies,or tau-mediated neurodegeneration, is not clear. By generating P301S tautransgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO)background, here we show that P301S/E4 mice have significantly higher taulevels in the brain and a greater extent of somatodendritic tau redistributionby three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. Bynine months of age, P301S mice with different ApoE genotypes display distinctphosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice developmarkedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3mice, whereas P301S/EKO mice are largely protected from these changes. Invitro, E4-expressing microglia exhibit higher innate immune reactivity afterlipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons withE4-expressing mixed glia results in a significantly higher level oftumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronalviability compared withneuron/E2 and neuron/E3 co-cultures. Neuronsco-cultured with EKO glia showed the greatest viability with the lowest levelof secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3,E4) also leads to some neuronal damage and death compared with the absence ofApoE, with ApoE4 exacerbating the effect. In individuals with a sporadicprimary tauopathy, the presence of an ε4 allele is associated with more severeregional neurodegeneration. In individuals who are positive for amyloid-βpathology with symptomatic Alzheimer disease who usually have taupathology, ε4-carriers demonstrate greater rates of diseaseprogression.Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation,and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

第五位：研究揭示AD中TREM2对维持小胶质细胞代谢稳态极为关键

Cell. 2017 Aug 10;170(4):649-663.e13. TREM2 MaintainsMicroglial Metabolic Fitness in Alzheimer's Disease.

Abstract

Elevated risk of developing Alzheimer's disease (AD)is associated with hypomorphic variants of TREM2, a surface receptor requiredfor microglial responses to neurodegeneration, including proliferation,survival, clustering, and phagocytosis. How TREM2 promotes such diverseresponses is unknown. Here, we find that microglia in AD patients carryingTREM2 risk variants and TREM2-deficient mice with AD-like pathology haveabundant autophagic vesicles, as do TREM2-deficient macrophages undergrowth-factor limitation or endoplasmic reticulum (ER) stress. Combinedmetabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy todefective mammalian target of rapamycin (mTOR) signaling, which affects ATPlevels and biosynthetic pathways. Metabolic derailment and autophagy wereoffset in vitro through Dectin-1, a receptor that elicits TREM2-likeintracellular signals, and cyclocreatine, a creatine analog that can supplyATP. Dietary cyclocreatine tempered autophagy, restored microglial clusteringaround plaques, and decreased plaque-adjacent neuronal dystrophy inTREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglialresponses during AD by sustaining cellular energetic and biosyntheticmetabolism.

第六位：研究发现遗传性AD基因突变引起Aβ长度改变的分子生物学机制

Cell. 2017 Jul 27;170(3):443-456.e14. Alzheimer's-CausingMutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions.

Abstract

Alzheimer's disease (AD)-linked mutations inPresenilins (PSEN) and the amyloid precursor protein (APP) lead to productionof longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental tothe disease; however, the underlying mechanism remains elusive. Here, weshow that substrate shortening progressively destabilizes the consecutiveenzyme-substrate (E-S) complexes that characterize the sequentialγ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutationsfurther destabilize labile E-S complexes and thereby promote generation oflonger Aβ peptides. Similarly, destabilization of wild-type E-S complexes bytemperature, compounds, or detergent promotes release of amyloidogenic Aβ. Incontrast, E-Aβ_n stabilizers increase γ-secretase processivity.Our work presents a unifying model for how PSEN or APP mutations enhanceamyloidogenic Aβ production, suggests that environmental factors may increaseAD risk, and provides the theoretical basis for the development ofγ-secretase/substrate stabilizing compounds for the prevention of AD.

第七位：病理研究发现美国足球运动员慢性创伤性脑病的发生风险显著增加

JAMA. 2017 Jul 25;318(4):360-370. ClinicopathologicalEvaluation of Chronic Traumatic Encephalopathy in Players of American Football.

Abstract

IMPORTANCE:

Players of American footballmay be at increased risk of long-term neurological conditions, particularlychronic traumatic encephalopathy (CTE).

OBJECTIVE:

To determine theneuropathological and clinical features of deceased football players with CTE.

DESIGN, SETTING, AND PARTICIPANTS:

Case series of 202 football players whose brains were donated forresearch. Neuropathological evaluations and retrospective telephone clinicalassessments (including head trauma history) with informants were performed blinded.Online questionnaires ascertained athletic and military history.

EXPOSURES:

Participation in Americanfootball at any level of play.

MAIN OUTCOMES AND MEASURES:

Neuropathologicaldiagnoses of neurodegenerative diseases, including CTE, based on defineddiagnostic criteria; CTE neuropathological severity (stages I to IV ordichotomized into mild [stages I and II] and severe [stages III and IV]);informant-reported athletic history and, for players who died in 2014 or later,clinical presentation, including behavior, mood, and cognitive symptoms anddementia.

RESULTS:

Among 202 deceased formerfootball players (median age at death, 66 years [interquartile range, 47-76years]), CTE was neuropathologically diagnosed in 177 players (87%; median ageat death, 67 years [interquartile range, 52-77 years]; mean years of footballparticipation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 highschool (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8Canadian Football League (88%), and 110 of 111 National Football League (99%)players. Neuropathological severity of CTE was distributed across the highestlevel of play, with all 3 former high school players having mild pathology andthe majority of former college (27 [56%]), semiprofessional (5 [56%]), andprofessional (101 [86%]) players having severe pathology. Among 27 participantswith mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23(85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participantswith severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80(95%) had cognitive symptoms, and 71 (85%) had signs of dementia.

CONCLUSIONS AND RELEVANCE:

In aconvenience sample of deceased football players who donated their brains forresearch, a high proportion had neuropathological evidence of CTE, suggestingthat CTE may be related to prior participation in football.

第八位：研究发现正常老年人中Aβ淀粉样蛋白水平增加和认知功能下降显著相关。

JAMA. 2017 Jun 13;317(22):2305-2316. AssociationBetween Elevated Brain Amyloid and Subsequent Cognitive Decline AmongCognitively Normal Persons.

Abstract

IMPORTANCE:

Among cognitively normalindividuals, elevated brain amyloid (defined by cerebrospinal fluid assays orpositron emission tomography regional summaries) can be related to risk forlater Alzheimer-relatedcognitive decline.

OBJECTIVE:

To characterize and quantifythe risk for Alzheimer-related cognitive decline among cognitivelynormal individuals with elevated brain amyloid.

DESIGN, SETTING, AND PARTICIPANTS:

Exploratory analyses were conducted with longitudinal cognitiveand biomarker data from 445 cognitively normal individuals in the United Statesand Canada. Participants were observed from August 23, 2005, to June 7, 2016,for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximumfollow-up, 10.3 years) as part of the Alzheimer's DiseaseNeuroimaging Initiative (ADNI).

EXPOSURES:

Individuals were classified atbaseline as having normal (n = 243) or elevated (n = 202) brain amyloid usingpositron emission tomography amyloid imaging or a cerebrospinal fluid assay ofamyloid β.

MAIN OUTCOMES AND MEASURES:

Outcomesincluded scores on the Preclinical Alzheimer CognitiveComposite (PACC; a sum of 4 baseline standardized z scores, which decreaseswith worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30[best] points), Clinical Dementia Rating Sum of Boxes (CDR-Sum of Boxes; 0[best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to25 [best] story units).

RESULTS:

Among the 445 participants (243with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9)years, mean education was 16.4 (2.7) years, and 52% were women. The mean scorefor PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR-Sum ofBoxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Comparedwith the group with normal amyloid, those with elevated amyloid had worse meanscores at 4 years on the PACC (mean difference, 1.51 points [95% CI,0.94-2.10]; P < .001), MMSE (mean difference, 0.56 points [95% CI,0.32-0.80]; P < .001), and CDR-Sum of Boxes (mean difference, 0.23 points[95% CI, 0.08-0.38]; P = .002). For Logical Memory Delayed Recall,between-group score was not statistically significant at 4 years (meandifference, 0.73 story units [95% CI, -0.02 to 1.48]; P = .056).

CONCLUSIONS AND RELEVANCE:

Exploratoryanalyses of a cognitively normal cohort followed up for a median of 3.1 yearssuggest that elevation in baseline brain amyloid level, compared with normalbrain amyloid level, was associated with higher likelihood of cognitivedecline, although the findings are of uncertain clinical significance. Furtherresearch is needed to assess the clinical importance of these differences andmeasure longer-term associations.

第九位：研究发现了不同临床亚型AD的淀粉样蛋白纤维结构存在显著差异

Nature. 2017 Jan 12;541(7636):217-221.Structural variation in amyloid-β fibrils from Alzheimer'sdisease clinical subtypes.

Abstract

Aggregation of amyloid-β peptides into fibrils or otherself-assembled states is central to the pathogenesis of Alzheimer'sdisease. Fibrils formed in vitro by 40- and 42-residue amyloid-β peptides (Aβ40and Aβ42) are polymorphic, with variations in molecular structure that dependon fibril growth conditions. Recent experiments suggest that variations inamyloid-β fibril structure in vivo may correlate with variations in Alzheimer'sdisease phenotype, in analogy to distinct prion strains that areassociated with different clinical and pathological phenotypes. Here weinvestigate correlations between structural variation and Alzheimer'sdisease phenotype using solid-state nuclear magnetic resonance (ssNMR)measurements on Aβ40 and Aβ42 fibrils prepared by seeded growth from extractsofAlzheimer's disease brain cortex. We compared two atypical Alzheimer'sdisease clinical subtypes-the rapidly progressive form (r-AD) and theposterior cortical atrophy variant (PCA-AD)-with a typical prolonged-durationform (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18individuals, we find that a single Aβ40 fibril structure is most abundant insamples from patients with t-AD and PCA-AD, whereas Aβ40 fibrils from r-ADsamples exhibit a significantly greater proportion of additional structures.Data for Aβ42 fibrils indicate structural heterogeneity in most samples fromall patient categories, with at least two prevalent structures. These resultsdemonstrate the existence of a specific predominant Aβ40 fibril structure int-AD and PCA-AD, suggest that r-AD may relate to additional fibril structuresand indicate that there is a qualitative difference between Aβ40 and Aβ42aggregates in the brain tissue of patients with Alzheimer's disease.

第十位：研究发现中年阶段血管风险因素和大脑淀粉样蛋白沉积密切相关。

JAMA. 2017Apr 11;317(14):1443-1450. Association Between Midlife Vascular RiskFactors and Estimated Brain Amyloid Deposition.

Abstract

IMPORTANCE:

Midlife vascular risk factors have been associated with late-lifedementia. Whether these risk factors directly contribute to brain amyloiddeposition is less well understood.

OBJECTIVE:

To determine if midlife vascular risk factors are associated withlate-life brain amyloid deposition, measured using florbetapir positronemission tomography (PET).

DESIGN,SETTING, AND PARTICIPANTS:

The Atherosclerosis Risk in Communities (ARIC)-PET Amyloid ImagingStudy, a prospective cohort study among 346 participants without dementia in 3US communities (Washington County, Maryland; Forsyth County, North Carolina;and Jackson, Mississippi) who have been evaluated for vascular risk factors andmarkers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emissiontomography image analysis was completed in 2015.

EXPOSURES:

Vascular risk factors at ARIC baseline (age 45-64 years; riskfactors included body mass index ≥30, current smoking, hypertension, diabetes,and total cholesterol ≥200 mg/dL) were evaluated in multivariable modelsincluding age, sex, race, APOE genotype, and educational level.

MAINOUTCOMES AND MEASURES:

Standardized uptake value ratios (SUVRs) were calculated from PETscans and a mean global cortical SUVR was calculated. Elevated florbetapir (definedas a SUVR >1.2) was the dependent variable.

RESULTS:

Among322 participants without dementia and with nonmissing midlife vascular riskfactors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR(elevated in 164 [50.9%] participants) was measured more than 20 years later(median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) whenparticipants were between 67 and 88 (mean, 76) years old. Elevated body massindex in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95%CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123had 1, and 134 had 2 or more; a higher number of midlife risk factors wasassociated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4%[n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with0 midlife vascular risk factors, the OR for elevated SUVR associated with 1vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascularrisk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factorinteractions were found. Late-life vascular risk factors were not associatedwith late-life brain amyloid deposition (for ≥2 late-life vascular risk factorsvs 0: OR, 1.66; 95% CI, 0.75-3.69).

CONCLUSIONSAND RELEVANCE:

An increasing number of midlife vascular risk factors was significantlyassociated with elevated amyloid SUVR; this association was not significant forlate-life risk factors. These findings are consistent with a role of vascular diseasein the development of Alzheimer disease.

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