2018年阿尔茨海默病十大研究突破

一.   《Nature》：体细胞APP基因重组可能是散发性AD的遗传学根源。

体细胞基因重组是通过改变生殖系DNA序列从而改变遗传密码的一种方式。在大脑中也存在广泛的体细胞基因突变。其中跟AD相关的APP基因就存在频繁的体细胞基因重组。这篇文章发现了AD的神经元和正常的神经元中都存在APP的基因重组，但是散发性AD的神经元的基因重组比正常神经元的APP基因重组复杂，产生的基因组cDNA异质性更强，从而引起了跟家族性AD相关的各种突变。

摘要：The diversity and complexity of the human brain are widelyassumed to be encoded within a constant genome. Somatic gene recombination,which changes germline DNA sequences to increase molecular diversity, couldtheoretically alter this code but has not been documented in the brain, to ourknowledge. Here we describe recombination of the Alzheimer's disease-relatedgene APP, which encodes amyloid precursor protein, in human neurons, occurringmosaically as thousands of variant 'genomic cDNAs' (gencDNAs). gencDNAs lackedintrons and ranged from full-length cDNA copies of expressed, brain-specificRNA splice variants to myriad smaller forms that contained intra-exonicjunctions, insertions, deletions, and/or single nucleotide variations. DNA insitu hybridization identified gencDNAs within single neurons that were distinctfrom wild-type loci and absent from non-neuronal cells. Mechanistic studiessupported neuronal 'retro-insertion' of RNA to produce gencDNAs; this processinvolved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadicAlzheimer's disease showed increased gencDNA diversity, including elevenmutations known to be associated with familial Alzheimer's disease that wereabsent from healthy neurons. Neuronal gene recombination may allow'recording' of neural activity for selective 'playback' of preferred genevariants whose expression bypasses splicing; this has implications for cellulardiversity, learning and memory, plasticity, and diseases of the human brain.

参考文献：Somatic APP gene recombination inAlzheimer's disease and normal neurons. Nature. 2018 Nov;563(7733):639-645.

二.   《Nature》：大脑中的Aβ病理沉积可以通过Aβ的“种子”进行医源性传播。

       本研究的结论是Aβ的沉积可以通过接触了Aβ的肽段而在大脑中播散，而结论并不是AD可以通过接触了Aβ的肽段而引起。事实上，有Aβ的沉积还不一定就是AD，只是说AD的风险增加了。这一研究跟既往的研究结论是相符的，Aβ的沉积可以通过Aβ的“种子”进行医源性传播。Aβ和prion还是不一样的，prion可以直接引起CJD，但是Aβ即使在大脑中沉积了也未必就是AD。

要：We previously reported¹ the presence of amyloid-β protein(Aβ) deposits in individuals with Creutzfeldt-Jakob disease (CJD) who had been treated during childhood withhuman cadaveric pituitary-derived growth hormone (c-hGH) contaminated withprions. The marked deposition ofparenchymal and vascular Aβ in these relatively young individuals withtreatment-induced (iatrogenic) CJD (iCJD), in contrast to other prion-disease patients and population controls, alliedwith the ability of Alzheimer's disease brain homogenates to seed Aβ deposition in laboratoryanimals, led us to argue that the implicated c-hGH batches might have beencontaminated with Aβ seeds as well as with prions. However, this wasnecessarily an association, and not an experimental, study in humans andcausality could not be concluded. Given the public health importance of ourhypothesis, we proceeded to identify and biochemically analyse archived vialsof c-hGH. Here we show that certain c-hGH batches to which patients with iCJDand Aβ pathology were exposed have substantial levels of Aβ₄₀, Aβ₄₂ and tau proteins, and that thismaterial can seed the formation of Aβ plaques and cerebral Aβ-amyloidangiopathy in intracerebrally inoculated mice expressing a mutant, humanizedamyloid precursor protein. These results confirm the presence of Aβ seeds inarchived c-hGH vials and are consistent with the hypothesized iatrogenic humantransmission of Aβ pathology. This experimental confirmation has implicationsfor both the prevention and the treatment of Alzheimer's disease, andshould prompt a review of the risk of iatrogenic transmission of Aβ seeds bymedical and surgical procedures long recognized to pose a risk of accidentalprion transmission^2,3.

参考文献：Transmission of amyloid-β protein pathologyfrom cadaveric pituitary growth hormone. Nature. 2018 Dec;564(7736):415-419.

三.   《Nature》：脑膜淋巴管在衰老和AD发生中具有重要的作用。

本研究接着前面几年关于大脑中存在淋巴系统（管道）的新发现，对脑膜淋巴管在衰老和AD中的作用进行了研究。研究人员发现破坏脑膜淋巴管加剧衰老相关的认知改变，而且也会加重AD模型小鼠的Aβ沉积。

摘要：Ageing is a major risk factor for many neurologicalpathologies, but its mechanisms remain unclear. Unlike other tissues, theparenchyma of the central nervous system (CNS) lacks lymphatic vasculature andwaste products are removed partly through a paravascular route. (Re)discoveryand characterization of meningeal lymphatic vessels has prompted an assessmentof their role in waste clearance from the CNS. Here we show that meningeallymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitialfluids) into the cervical lymph nodes in mice. Impairment of meningeallymphatic function slows paravascular influx of macromolecules into the brainand efflux of macromolecules from the interstitial fluid, and induces cognitiveimpairment in mice. Treatment of aged mice with vascular endothelial growthfactor C enhances meningeal lymphatic drainage of macromolecules from thecerebrospinal fluid, improving brain perfusion and learning and memoryperformance. Disruption of meningeallymphatic vessels in transgenic mouse models of Alzheimer's disease promotesamyloid-β deposition in the meninges, which resembles human meningealpathology, and aggravates parenchymal amyloid-β accumulation. Meningeallymphatic dysfunction may be an aggravating factor in Alzheimer's diseasepathology and in age-associated cognitive decline. Thus, augmentation ofmeningeal lymphatic function might be a promising therapeutic target forpreventing or delaying age-associated neurological diseases.

参考文献：Functional aspects of meningeal lymphaticsin ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191.

四.   《Nature medicine》：研究人员在iPSC中揭示了APOE4的致病机制并发现了一个APOE4的小分子纠正化合物可以改善APOE4的毒性作用。

本研究发现了APOE4表达的iPSC神经元出现各种AD特异性的病理改变，包括Aβ、tau和GABA能神经元的变性。有趣的是Aβ的增加只发生在人类神经元中，而在其他种属神经元中不存在。重要的是研究人员发现了APOE4的小分子调节物可以减轻其引起的各种病理改变。

摘要：Efforts to develop drugs for Alzheimer's disease (AD) haveshown promise in animal studies, only to fail in human trials, suggesting apressing need to study AD in human model systems. Using human neurons derivedfrom induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), avariant of the APOE gene product and the major genetic risk factor for AD, wedemonstrated that ApoE4-expressing neurons had higher levels of tauphosphorylation, unrelated to their increased production of amyloid-β (Aβ)peptides, and that they displayed GABAergic neuron degeneration. ApoE4increased Aβ production in human, but not in mouse, neurons. Converting ApoE4to ApoE3 by gene editing rescued these phenotypes, indicating the specificeffects of ApoE4. Neurons that lacked APOE behaved similarly to thoseexpressing ApoE3, and the introduction of ApoE4 expression recapitulated thepathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons witha small-molecule structure corrector ameliorated the detrimental effects,thus showing that correcting the pathogenic conformation of ApoE4 is a viabletherapeutic approach for ApoE4-related AD.

参考文献： Gain of toxic apolipoprotein E4effects in human iPSC-derived neurons is ameliorated by a small-moleculestructure corrector. Nat Med. 2018 May;24(5):647-657.

五.   《Nature》：验血知AD—研究发现血浆Aβ标志物检测可以预测大脑中的Aβ沉积。

这项研究的价值就在于找到了代替PET成像检测Aβ病理的一种方式，这种方式的优势是价格低廉、准确度高、操作性强，临床应用价值大。在血浆里检测Aβ总是比做7000多元的PET成像要好吧，后者的辐射危害和价格昂贵是很多人放弃PET检测的重要原因。

摘要：To facilitate clinical trials of disease-modifying therapiesfor Alzheimer's disease, which are expected to be most efficacious at theearliest and mildest stages of the disease, supportive biomarker information isnecessary. The only validated methods for identifying amyloid-β deposition inthe brain-the earliest pathological signature of Alzheimer's disease-areamyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-βin cerebrospinal fluid. Therefore, a minimally invasive, cost-effectiveblood-based biomarker is desirable. Despite much effort, to our knowledge, nostudy has validated the clinical utility of blood-based amyloid-β markers. Herewe demonstrate the measurement of high-performance plasma amyloid-β biomarkersby immunoprecipitation coupled with mass spectrometry. The ability of amyloid-βprecursor protein (APP)_669-711/amyloid-β (Aβ)_1-42 and Aβ_1-40/Aβ_1-42 ratios, and their composites, topredict individual brain amyloid-β-positive or -negative status was determinedby amyloid-β-PET imaging and tested using two independent data sets: adiscovery data set (Japan, n = 121) and a validation data set (Australia,n = 252 including 111 individuals diagnosed using ¹¹C-labelled Pittsburgh compound-B (PIB)-PET and 141 usingother ligands). Both data sets included cognitively normal individuals,individuals with mild cognitive impairment and individuals with Alzheimer'sdisease. All test biomarkers showed highperformance when predicting brain amyloid-β burden. In particular, thecomposite biomarker showed very high areas under the receiver operatingcharacteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 andvalidation, 94.1%, n = 111) with an accuracy approximately equal to 90% whenusing PIB-PET as a standard of truth. Furthermore, test biomarkers werecorrelated with amyloid-β-PET burden and levels of Aβ_1-42 in cerebrospinal fluid. These resultsdemonstrate the potential clinical utility of plasma biomarkers in predictingbrain amyloid-β burden at an individual level. These plasma biomarkers alsohave cost-benefit and scalability advantages over current techniques,potentially enabling broader clinical access and efficient population screening.

参考文献：High performance plasma amyloid-βbiomarkers for Alzheimer's disease. Nature. 2018 Feb 8;554(7691):249-254.

六.   《Neuron》：毒性Aβ的策反—Aβ的生理功能可能是对抗大脑疱疹病毒的感染

       以前的研究就发现，疱疹病毒感染增加AD的发生风险。在这项研究中，研究人员揭示了Aβ寡聚体能够和疱疹病毒表面糖蛋白结合并起到对抗病毒感染的作用。因此，Aβ沉积很有可能不是AD的致病因子，而是大脑对抗病毒感染后的结果。

摘要：Amyloid-β peptide (Aβ) fibrilization and deposition asβ-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reportedAβ is an innate immune protein that protects against fungal and bacterialinfections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus,infection can seed and dramatically accelerate β-amyloid deposition. Here, weshow Aβ oligomers bind herpesvirus surface glycoproteins, acceleratingβ-amyloid deposition and leading to protective viral entrapment activity in5XFAD mouse and 3D human neuralcell culture infection models against neurotropicherpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae arelinked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNSinnate immunity, and suggest an AD etiological mechanism in which herpesviridaeinfection may directly promote Aβ amyloidosis.

参考文献：Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded byHerpesviridae to Protect against Brain Infection. Neuron. 2018 Jul11;99(1):56-63.

七.   《Science》：运动通过促进成年神经再生和BDNF分泌进而改善AD小鼠的认知功能。

本项研究的意义就在于揭示了运动改善AD认知的机制是促进成年神经新生和BDNF的分泌。

摘要：Adult hippocampal neurogenesis (AHN) is impaired before the onsetof Alzheimer's disease (AD) pathology. We found that exercise providedcognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN andelevating levels of brain-derived neurotrophic factor (BDNF). Neitherstimulation of AHN alone, nor exercise, in the absence of increased AHN,ameliorated cognition. We successfully mimicked the beneficial effects ofexercise on AD mice by genetically and pharmacologically inducing AHN incombination with elevating BDNF levels. Suppressing AHN later led to worsenedcognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise,enhancing AHN and elevating BDNF levels, may improve cognition in AD.Furthermore, applied at early stages of AD, these mimetics may protect againstsubsequent neuronal cell death.

参考文献：Combined adult neurogenesis and BDNF mimic exercise effects on cognitionin an Alzheimer's mouse model. Science. 2018 Sep 7;361(6406).

八.   《Nature medicine》：研究发现了与AD相关的新遗传位点PM20D1。

这项研究的主要发现是揭示了PM20D1可能是与AD相关的新位点。这个位点的特征是其与AD中基因的甲基化和基因表达相关。研究人员除了进行EWAS研究，还做了机制研究，证明PM20D1确实和AD的发生相关。

要：The chances to develop Alzheimer's disease (AD) result from acombination of genetic and non-genetic risk factors ¹ , the latter likely being mediated byepigenetic mechanisms ² .In the past, genome-wide association studies (GWAS) have identified animportant number of risk loci associated with AD pathology ³ , but a causal relationship remainsdifficult to establish. In contrast, locus-specific or epigenome-wideassociation studies (EWAS) have revealed site-specific epigenetic alterations,which provide mechanistic insights for a particular risk gene but often lackthe statistical power of GWAS ⁴ .Here, combining both approaches, we report a previously unidentifiedassociation of the peptidase M20-domain-containing protein 1 (PM20D1) with AD.We find that PM20D1 is a methylation and expression quantitative trait locuscoupled to an AD-risk associated haplotype, which displays enhancer-likecharacteristics and contacts the PM20D1 promoter via a haplotype-dependent,CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increasedfollowing AD-related neurotoxic insults at symptomatic stages in the APP/PS1mouse model of AD and in human patients with AD who are carriers of thenon-risk haplotype. In line, geneticallyincreasing or decreasing the expression of PM20D1 reduces and aggravatesAD-related pathologies, respectively. These findings suggest that in aparticular genetic background, PM20D1 contributes to neuroprotection against AD.

参考文献：PM20D1 is a quantitative trait locusassociated with Alzheimer's disease. Nat Med. 2018 May;24(5):598-603.

九.   《Nature》：固有免疫记忆可能影响Aβ淀粉样蛋白的沉积。

本研究主要探讨了固有免疫记忆在大脑病理异常中的作用。研究人员发现通过免疫培训可以加重大脑的Aβ淀粉样沉积，而免疫耐受可以减轻Aβ淀粉样沉积。

摘要：Innate immune memory is a vital mechanism of myeloid cellplasticity that occurs in response to environmental stimuli and alterssubsequent immune responses. Two types of immunological imprinting can bedistinguished-training and tolerance. These are epigenetically mediated andenhance or suppress subsequent inflammation, respectively. Whether immunememory occurs in tissue-resident macrophages in vivo and how it may affectpathology remains largely unknown. Here we demonstrate that peripherallyapplied inflammatory stimuli induce acute immune training and tolerance in thebrain and lead to differential epigenetic reprogramming of brain-residentmacrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer'spathology, immune training exacerbates cerebral β-amyloidosis and immunetolerance alleviates it; similarly, peripheral immune stimulation modifiespathological features after stroke. Our results identify immune memory in thebrain as an important modifier of neuropathology.

参考文献：Innate immune memory in the brain shapesneurological disease hallmarks. Nature. 2018 Apr;556(7701):332-338.

十.   《Nature medicine》：研究人员“刻画”了Aβ斑块引起神经元纤维缠结（NFTs）形成的可能机制。

本项研究主要是通过在含Aβ斑块模型小鼠中注射人AD大脑中的病理性tau蛋白，发现在小鼠大脑中形成了各种tau蛋白的病理现象：包括营养不良性神经突起、神经元纤维缠结和神经纤维网线。这些tau的异常改变是与Aβ斑块直接相关的。

摘要：Alzheimer's disease (AD) is characterized by extracellularamyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exactmechanistic link between these two AD lesions remains enigmatic. Through injection of humanAD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse modelsthat do not overexpress tau, we recapitulated the formation of three majortypes of AD-relevant tau pathologies: tau aggregates in dystrophic neuritessurrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) andneuropil threads (NTs). These distinct tau pathologies have differenttemporal onsets and functional consequences on neural activity and behavior.Notably, we found that Aβ plaques created a unique environment that facilitatedthe rapid amplification of proteopathic AD-tau seeds into large tau aggregates,initially appearing as NP tau, which was followed by the formation and spreadof NFTs and NTs, likely through secondary seeding events. Our study providesinsights into a new multistep mechanism underlying Aβ plaque-associated taupathogenesis.

参考文献：Amyloid-β plaques enhance Alzheimer's braintau-seeded pathologies by facilitating neuritic plaque tau aggregation. NatMed. 2018 Jan;24(1):29-38.

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