Acta Neuropathologica Communications最新文献

{"title":"A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G₄C₂)₆₆ mouse model.","authors":"Emily G Thompson, Olivia Spead, Suleyman C Akerman, Carrie Curcio, Benjamin L Zaepfel, Erica R Kent, Thomas Philips, Balaji G Vijayakumar, Anna Zacco, Weibo Zhou, Guhan Nagappan, Jeffrey D Rothstein","doi":"10.1186/s40478-024-01911-y","DOIUrl":"10.1186/s40478-024-01911-y","url":null,"abstract":"<p><p>The G₄C₂ hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G₄C₂ hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G₄C₂)₆₆ mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G₄C₂) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"203"},"PeriodicalIF":6.2,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3-Dimensional morphological characterization of neuroretinal microglia in Alzheimer's disease via machine learning.","authors":"Wissam B Nassrallah, Hao Ran Li, Lyden Irani, Printha Wijesinghe, Peter William Hogg, Lucy Hui, Jean Oh, Ian R Mackenzie, Veronica Hirsch-Reinshagen, Ging-Yuek Robin Hsiung, Wellington Pham, Sieun Lee, Joanne A Matsubara","doi":"10.1186/s40478-024-01898-6","DOIUrl":"10.1186/s40478-024-01898-6","url":null,"abstract":"<p><p>Alzheimer's Disease (AD) is a debilitating neurodegenerative disease that affects 47.5 million people worldwide. AD is characterised by the formation of plaques containing extracellular amyloid-β (Aβ) and neurofibrillary tangles composed of hyper-phosphorylated tau proteins (pTau). Aβ gradually accumulates in the brain up to 20 years before the clinical onset of dementia, making it a compelling candidate for early detection of AD. It has been shown that there is increased deposition of Aβs in AD patients' retinas. However, little is known about microglia's ability to function and clear Aβ within the retina of AD and control eyes. We labelled microglia with ionised calcium-binding adaptor molecule 1 (IBA-1) in AD and age-matched control donor retinas. We then used interactive machine learning to segment individual microglia in 3D. In the temporal mid-peripheral region, we found that the number of microglia was significantly lower in AD retinas compared to controls. Unexpectedly, the size of the microglia was significantly larger in the AD retinas compared to controls. We also labelled retinal microglia for Cluster of Differentiation 68 (CD68), a transmembrane glycoprotein expressed by cells in the monocyte lineage and a marker of phagocytic activity and activated microglia. The size of CD68 + cells was statistically different between AD and control microglial, with CD68 + cells being larger in AD. In contrast, there was no difference in either size or shape for CD68- microglia between the two groups, suggesting an important difference in the active states of CD68 + microglia in AD retina. There was also significantly increased CD68 immunoreactivity in individual microglia within the AD group. Overall, this study reveals unique differences in the size and activity of the retinal microglia, which may relate to their potential chronic activation due to increased levels of Aβs in the AD retina.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"202"},"PeriodicalIF":6.2,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain.","authors":"Xi-Biao He, Fang Guo, Wei Zhang, Jiacheng Fan, Weidong Le, Qi Chen, Yongjun Ma, Yong Zheng, Sang-Hun Lee, Hui-Jing Wang, Yi Wu, Qinming Zhou, Rui Yang","doi":"10.1186/s40478-024-01912-x","DOIUrl":"10.1186/s40478-024-01912-x","url":null,"abstract":"<p><p>Midbrain dopamine (mDA) neurons participate in a wide range of brain functions through an intricate regulation of DA biosynthesis. The epigenetic factors and mechanisms in this process are not well understood. Here we report that histone demethylase JMJD3 is a critical regulator for DA biosynthesis in adult mouse mDA neurons. Mice carrying Jmjd3 conditional knockout or undergoing pharmaceutical inhibition of JMJD3 showed consistent reduction of DA content in midbrain and striatum. Histological examination of both mice confirmed that TH and NURR1, two key molecules in DA biosynthesis pathway, were decreased in mDA neurons. Mechanistic experiments in vivo and in vitro further demonstrated that the transcriptions of Th and Nurr1 in mDA neurons were suppressed by JMJD3 deficiency, because of increased repressive H3K27me3 and attenuated bindings of JMJD3 and NURR1 on the promoters of both genes. On behavioral level, a significant prolonged inflammation-induced mechanical hyperalgesia was found in conditional knockout mice regardless of sex and age, whereas motor function appeared to be intact. Our findings establish a novel link between DA level in mDA neurons with intrinsic JMJD3 activity, and suggest prolonged chronic inflammatory pain as a major loss-of-function consequence.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"201"},"PeriodicalIF":6.2,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adequate post-ischemic reperfusion of the mouse brain requires endothelial NFAT5.","authors":"Reiner Kunze, Paul Wacker, Paula Breuer, Emil Nasyrov, Ivan M Kur, Andreas Weigert, Andreas H Wagner, Hugo H Marti, Thomas Korff","doi":"10.1186/s40478-024-01918-5","DOIUrl":"10.1186/s40478-024-01918-5","url":null,"abstract":"<p><p>Severity and outcome of strokes following cerebral hypoperfusion are significantly influenced by stress responses of the blood vessels. In this context, brain endothelial cells (BEC) regulate inflammation, angiogenesis and the vascular resistance to rapidly restore perfusion. Despite the relevance of these responses for infarct volume and tissue recovery, their transcriptional control in BEC is not well characterized. We revealed that oxygen and nutrient-deprived BEC activate nuclear factor of activated T-cells 5 (NFAT5)-a transcription factor that adjusts the cellular transcriptome to cope with environmental stressors. We hypothesized that NFAT5 controls the expression of genes regulating the response of BEC in the ischemic brain. The functional relevance of NFAT5 was assessed in mice, allowing the conditional EC-specific knock-out of Nfat5 (Nfat5^(EC)-/-). Cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) followed reperfusion up to 28 days. While loss of endothelial Nfat5 did not evoke any phenotypic abnormalities in mice under control conditions, infarct volumes, neurological deficits and the degree of brain atrophy were significantly pronounced following MCAO as compared to control animals (Nfat5^fl/fl). In contrast, MCAO-induced edema formation, inflammatory processes and angiogenesis were not altered in Nfat5^(EC)-/- mice. RNAseq analyses of cultured BEC suggested that loss of NFAT5 impairs the expression of Kcnj2 encoding a potassium channel that may affect reperfusion. In fact, lower levels of KCNJ2 were detected in arterial endothelial cells of Nfat5^(EC)-/- versus Nfat5^fl/fl mice. Laser speckle contrast imaging of the brain revealed an impaired perfusion recovery in Nfat5^(EC)-/- versus Nfat5^fl/fl mice after MCAO.Collectively, NFAT5 in arterial BEC is required for an adequate reperfusion response after brain ischemia that is presumably dependent on the maintenance of Kcnj2 expression. Consequently, impairment of the protective role of endothelial NFAT5 results in enlarged infarct sizes and more severe functional deficits of brain functions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"200"},"PeriodicalIF":6.2,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis.","authors":"Gracious D S Kasheke, Basmah A M Hendy, Gabriel G Dorighello, Nonthué A Uccelli, Jean-David M Gothié, Robyn J Novorolsky, Madison J Oulton, Jude Asainayagam, Adam I Makarov, Kaitlyn S Fraser, Vidyasagar Vuligonda, Martin E Sanders, Timothy E Kennedy, George S Robertson","doi":"10.1186/s40478-024-01904-x","DOIUrl":"10.1186/s40478-024-01904-x","url":null,"abstract":"<p><p>Evidence that myelin repair is crucial for functional recovery in multiple sclerosis (MS) led to the identification of bexarotene (BXT). This clinically promising remyelinating agent activates multiple nuclear hormone receptor subtypes implicated in myelin repair. However, BXT produces unacceptable hyperlipidemia. In contrast, IRX4204 selectively activates the retinoid X receptor (RXR). Given compelling links between RXR activation and increased myelin repair, we employed IRX4204 to investigate the impact of RXR agonism alone on functional recovery in mice subjected to experimental autoimmune encephalomyelitis (EAE). Since gait deficits are common in MS, we used machine learning to obtain highly sensitive and reliable measurements of sagittal hindleg joint movements for mice walking on a treadmill. IRX4204 not only blocked the progressive loss of knee and ankle movements but also reversed joint movement impairments in EAE mice. Our biochemical, transcriptional and histological measurements in spinal cord suggest these gait improvements reflect increased axon survival and remyelination and reduced inflammation. Using microglia, astrocytes and oligodendrocyte progenitor cells, we present additional data suggesting that IRX4204 may act on multiple glial subtypes to orchestrate myelin repair. These results inform the discovery of restorative neural therapeutics for MS by demonstrating that selective RXR agonism is sufficient for effective myelin repair. Moreover, our findings support the therapeutic potential of IRX4204 to promote functional recovery in MS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"197"},"PeriodicalIF":6.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.","authors":"Aya Jishi, Di Hu, Yutong Shang, Rihua Wang, Steven A Gunzler, Xin Qi","doi":"10.1186/s40478-024-01915-8","DOIUrl":"10.1186/s40478-024-01915-8","url":null,"abstract":"<p><p>Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficiency leads to mitochondrial dysfunction, including reduced membrane potential and increased reactive oxygen species (ROS) production upon administration of a stressor, which in turn promotes αSyn oligomerization. Mechanistically, BCKDK interacts with the NDUFS1 subunit of Complex I to stabilize its function. Loss of BCKDK disrupts this interaction, leading to Complex I destabilization and enhanced αSyn aggregation. Notably, restoring BCKDK expression in neuron-like cells rescues mitochondrial integrity and restores Complex I activity. Similarly, in patient-derived iPS cells differentiated to form dopaminergic neurons, NDUFS1 and phosphorylated aSyn levels are partially restored upon BCKDK expression. These findings establish a mechanistic link between BCKDK deficiency, mitochondrial dysfunction, and αSyn pathology in PD, positioning BCKDK as a potential therapeutic target to mitigate mitochondrial impairment and neurodegeneration in PD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"198"},"PeriodicalIF":6.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.","authors":"Olivia Keeley, Emma Mendoza, Druv Menon, Alyssa N Coyne","doi":"10.1186/s40478-024-01916-7","DOIUrl":"10.1186/s40478-024-01916-7","url":null,"abstract":"<p><p>Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent \"activation\" is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"199"},"PeriodicalIF":6.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline loss-of-function variant in the E3 ubiquitin ligase TRAF2 in a young adult patient with medulloblastoma: a case report.","authors":"Josh N Vo, Andrea Franson, Sebastian M Waszak, Yi-Mi Wu, Nicole Becker, Arul M Chinnaiyan, Dan R Robinson","doi":"10.1186/s40478-024-01896-8","DOIUrl":"10.1186/s40478-024-01896-8","url":null,"abstract":"<p><p>We identified a rare heterozygous germline loss-of-function variant in the tumor necrosis factor receptor-associated factor 2 (TRAF2) in a young adult patient diagnosed with medulloblastoma. This variant is located within the TRAF-C domain of the E3 ubiquitin ligase protein and is predicted to diminish the binding affinity of TRAF2 to upstream receptors and associated adaptor proteins. Integrative genomics revealed a biallelic loss of TRAF2 via partial copy-neutral loss-of-heterozygosity of 9q in the medulloblastoma genome. We further performed comparative analysis with an in-house cohort of 20 medulloblastomas sequenced using the same platform, revealing an atypical molecular profile of the TRAF2-associated medulloblastoma. Our research adds to the expanding catalog of genetic tumor syndromes that increase the susceptibility of carriers to MB.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"195"},"PeriodicalIF":6.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paradoxical attenuation of early amyloid-induced cognitive impairment and synaptic plasticity in an aged APP/Tau bigenic rat model.","authors":"Joshua T Emmerson, Sonia Do Carmo, Agustina Lavagna, Chunwei Huang, Tak Pan Wong, Julio C Martinez-Trujillo, A Claudio Cuello","doi":"10.1186/s40478-024-01901-0","DOIUrl":"10.1186/s40478-024-01901-0","url":null,"abstract":"<p><p>The combination of amyloid beta and tau pathologies leads to tau-mediated neurodegeneration in Alzheimer's disease. However, the relative contributions of amyloid beta and tau peptide accumulation to the manifestation of the pathological phenotype in the early stages, before the overt deposition of plaques and tangles, are still unclear. We investigated the longitudinal pathological effects of combining human-like amyloidosis and tauopathy in a novel transgenic rat model, coded McGill-R-APPxhTau. We compared the effects of individual and combined amyloidosis and tauopathy in transgenic rats by assessing the spatiotemporal progression of Alzheimer's-like amyloid and tau pathologies using biochemical and immunohistochemical methods. Extensive behavioral testing for learning and memory was also conducted to evaluate cognitive decline. Additionally, we investigated brain inflammation, neuronal cell loss, as well as synaptic plasticity through acute brain slice electrophysiological recordings and Western blotting. Evaluation of Alzheimer's-like amyloidosis and tauopathy, at the initial stages, unexpectedly revealed that the combination of amyloid pathology with the initial increment in phosphorylated tau exerted a paradoxical corrective effect on amyloid-induced cognitive impairments and led to a compensatory-like restoration of synaptic plasticity as revealed by electrophysiological evidence, compared to monogenic transgenic rats with amyloidosis or tauopathy. We discovered elevated CREB phosphorylation and increased expression of postsynaptic proteins as a tentative explanation for the improved hippocampal synaptic plasticity. However, this tau-induced protective effect on synaptic function was transient. As anticipated, at more advanced stages, the APPxhTau bigenic rats exhibited aggravated tau and amyloid pathologies, cognitive decline, increased neuroinflammation, and tau-driven neuronal loss compared to monogenic rat models of Alzheimer's-like amyloid and tau pathologies. The present findings propose that the early accumulation of phosphorylated tau may have a transient protective impact on the evolving amyloid pathology-derived synaptic impairments.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"193"},"PeriodicalIF":6.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pTau pathology in the retina of TAU58 mice: association with ganglion cell degeneration and implications on seeding and propagation of pTau from human brain lysates.","authors":"Grzegorz Walkiewicz, Alicja Ronisz, Simona Ospitalieri, Grigoria Tsaka, Sandra O Tomé, Rik Vandenberghe, Christine A F von Arnim, Frederic Rousseau, Joost Schymkowitz, Lies De Groef, Dietmar Rudolf Thal","doi":"10.1186/s40478-024-01907-8","DOIUrl":"10.1186/s40478-024-01907-8","url":null,"abstract":"<p><p>The accumulation of abnormal phosphorylated Tau protein (pTau) in neurons of the brain is a pathological hallmark of Alzheimer's disease (AD). PTau pathology also occurs in the retina of AD cases. Accordingly, questions arise whether retinal pTau can act as a potential seed for inducing cerebral pTau pathology and whether retinal pTau pathology causes degeneration of retinal neurons. To address these questions, we (1) characterized pTau pathology in the retina of TAU58 mice, (2) determined the impact of pTau pathology on retinal ganglion cell density, and (3) used this mouse model to test whether brain lysates from AD and/or non-AD control cases induce seeding in the retina and/or propagation into the brain. TAU58 mice developed retinal pTau pathology at 6 months of age, increasing in severity and extent with age. TAU58 mice showed reduced retinal ganglion cell density compared to wild-type mice, which declined with age and pTau pathology progression. Brain lysates from non-AD Braak neurofibrillary tangle (NFT) stage I controls increased retinal pTau pathology after subretinal injection compared to phosphate-buffered saline (PBS) but did not accelerate pTau pathology in the brain. In contrast, subretinally injected AD brain lysates accelerated pTau pathology in the retina and the contralateral superior colliculus. Subretinal injection of AD brain lysates, but not of non-AD brain, induced in this context a neuroinflammatory response in the retina and in the contralateral primary visual cortex. These results lead to the following conclusions: (1) Brain lysates from AD and non-AD sources can accelerate tauopathy within the retina. (2) The anterograde propagation of pTau pathology from the retina to the brain can be triggered by subretinal injections of AD brain lysates. (3) Such subretinal injections also provoke a neuroinflammatory response in both the retina and the visual cortex. (4) The accumulation of retinal pTau is associated with the degeneration of the involved ganglion cells, indicating that retinal tauopathy might contribute to vision impairment in the elderly and underscore the retina's potential role in spreading tau pathology to the brain.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"194"},"PeriodicalIF":6.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}