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.
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 transmission2,3.
参考文献：Transmission of amyloid-β protein pathologyfrom cadaveric pituitary growth hormone. Nature. 2018 Dec;564(7736):415-419.
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。
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.
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 Aβ1-40/Aβ1-42 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 Aβ1-42 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.
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.
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。
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.
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。
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.
27、神经科学临床和基础Learning & Memory亚群；