Our recent work on the prion protein and Na, K-ATPases (NKAs) led us to revisit data from over 50 years ago, which suggested similarities between vacuolation phenotypes in rodents poisoned with cardiac glycosides (CGs) a...Our recent work on the prion protein and Na, K-ATPases (NKAs) led us to revisit data from over 50 years ago, which suggested similarities between vacuolation phenotypes in rodents poisoned with cardiac glycosides (CGs) and spongiform degeneration in prion disease. At that time, this hypothesis was dismissed because the vacuolation observed in prion diseases affects neurons, whereas CG poisoning in rodent brains led to swellings of the endoplasmic reticulum (ER) in astrocytes. We speculated that this difference might be specific to rodents and document here that the vacuolation shifts to neurons in mice expressing a humanized NKA α1 subunit. Next, we investigated the molecular mechanisms that could cause similar ER vacuolation in human cells in vitro. We found that certain stressors-such as overexpression of NKA α subunits and exposure to specific toxins known to trigger the unfolded protein response-can induce a phenotype characterized by profound ER dilation that is most strikingly observed for the perinuclear space (PNS). The ion imbalance typically caused by functional NKAs does not contribute to this phenotype. In fact, it can occur even with the overexpression of catalytically inactive NKAs. Several lines of evidence, generated with pharmacological agents, ion-specific dyes, antagonists, and truncated expression constructs, suggest that a calcium leak channel in the ER, known as transient receptor potential vanilloid 2 (TRPV2), plays a role in this ER and PNS dilation. Additionally, we observed that the formation of these vacuoles coincides with a decrease in steady-state levels of the lipid kinase PIKFYVE, which is recognized for its role in endolysosomal fission and fusion processes. Finally, we found evidence of vacuoles in cryosectioned brains of prion-infected mice that can be filled with a fluorescent marker targeted at the ER and PNS. This raises the possibility that this vacuolation phenomenon contributes to spongiform degeneration seen in prion diseases.
Dourte M, Paître E, Bouchoucha M
… +10 more, Boyer E, Tomé SO, Doeraene E, Huart C, Leroy K, Thal DR, Decottignies A, Hanseeuw B, Suelves N, Kienlen-Campard P
Acta Neuropathol
· 2025 Jun · PMID 40536690
·
Full text
Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tang...Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g., EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OE's middle stratum and in the OB's olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Targeted treatments (ZnSO and AAVs) were applied at the OE level to assess the impact on tau pathology in the CNS. Complete stripping of the OE by intranasal administration of ZnSO led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human postmortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to aging or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.
Xin L, Nishihara H, Madarasz A
… +8 more, Pleskac P, Tran L, Ivan DC, Shimizu F, Aleandri S, Locatelli G, Luciani P, Proulx ST
Acta Neuropathol
· 2025 Jun · PMID 40536593
·
Full text
Patients with autoimmune inflammatory demyelinating diseases have been shown to present with trigeminal and cochlear nerve lesions restricted at the root transition zone, which contrasts with the relatively extensive dis...Patients with autoimmune inflammatory demyelinating diseases have been shown to present with trigeminal and cochlear nerve lesions restricted at the root transition zone, which contrasts with the relatively extensive distribution of lesions in optic neuritis. To better understand the mechanism underlying the different distribution pattern for cranial nerve lesions in these autoimmune neuroinflammatory diseases, we focused on the CNS-PNS transition zone (TZ) of the trigeminal and cochlear nerves in a MOG-driven active EAE model. These nerves were found to exhibit unique arrangements of anatomical barrier layers including the arachnoid and glia limitans, which affected cerebrospinal fluid (CSF) tracer distribution as well as CCR2 immune cell infiltration. Our data demonstrated that CCR2 immune cells accumulate at the TZ on both CNS side and PNS side of the trigeminal nerve and cochlear nerve, which mirror the locations of cranial nerve pathology observed clinically in patients with inflammatory demyelinating disease. On the other hand, the optic and olfactory nerves, which both lack a TZ, did not exhibit restrictions in immune cell localization. Overall, our results reconcile with the hypothesis that the segment of the cranial nerve that is exposed to CSF flow is more susceptible to CCR2 immune cell infiltration.
Tavares-Gomes L, Polidori M, Monney C
… +5 more, Neuhaus G, Vidondo B, Witz G, Hemphill A, Oevermann A
Acta Neuropathol
· 2025 Jun · PMID 40522474
·
Full text
Bacterial infections of the central nervous system (CNS) pose a significant threat to public health, especially with the growing challenge of antimicrobial resistance. Among these, Listeria monocytogenes (Lm) stands out...Bacterial infections of the central nervous system (CNS) pose a significant threat to public health, especially with the growing challenge of antimicrobial resistance. Among these, Listeria monocytogenes (Lm) stands out as a key pathogen, responsible for often fatal neurolisteriosis in humans and cattle. Emerging evidence highlights the distinct roles played by microglia, the resident macrophages of the CNS, and infiltrating monocyte-derived macrophages (MDM) during neuroinflammation. Using bovine models, we investigated the interactions between these two macrophage populations and Lm during infection. Our results show that Lm thrives in the cytosol of microglia, driving productive infection and facilitating bacterial spread. In contrast, MDM effectively sequesters Lm within the phagolysosomal system, limiting its replication and inducing a viable but non-culturable (VBNC) state without completely eliminating the pathogen. Listeriolysin O contributes to the dichotomy of Lm fate, determining whether Lm escapes into the cytosol or transitions to the VBNC state. These findings underscore the complexity of Lm-host dynamics in neurolisteriosis, emphasizing the distinct yet complementary roles of microglia and MDM in shaping CNS infection. By elucidating these mechanisms, our study offers new perspectives on the neurolisteriosis pathogenesis and opens avenues for innovative therapeutic approaches to combat bacterial neuroinfections.
Barrio T, Douet JY, Žáková D
… +9 more, Eraña H, Huor A, Cassard H, Alzuguren O, Lugan S, Aron N, Péran P, Castilla J, Andréoletti O
Acta Neuropathol
· 2025 Jun · PMID 40522345
·
Full text
The mutation E200K in the prion protein gene (PRNP) is the most common variant in genetic Creutzfeldt-Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesi...The mutation E200K in the prion protein gene (PRNP) is the most common variant in genetic Creutzfeldt-Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesis that the prion strains responsible for this form of the disease may be related to those involved in sporadic CJD (sCJD). In this study, we characterized the prion strains responsible for E200K gCJD cases from Slovakia (n = 12), Spain (n = 9), and France (n = 3) using transgenic mouse models expressing human prion protein (PrP). The cohort included patients with various PRNP genotypes: E200K-Met/Met, E200K-Met/E200K-Met, E200K-Met/Val, and E200K-Val/Val. Prion strain characterization revealed that the strains isolated from E200K gCJD cases corresponded to the two most common strains identified in sCJD cases: M1 and V2. Depending on the individual, these strains were either present as pure M1 or V2, or as a mixture of both (M1 + V2). Additionally, peripheral tissues from E200K-Met/Met patients (n = 4) and one E200K-Met/Val case were analyzed for prion infectivity and seeding activity. Similar to sCJD patients, low but detectable levels of prions were found in various peripheral tissues of E200K gCJD cases. Overall, our findings suggest that the prion strains and their distribution in the body are highly similar between E200K gCJD and sCJD patients. These similarities indicate that individuals carrying the E200K mutation may serve as a valuable model for understanding CJD pathogenesis during the preclinical phase of the disease.
Krech M, Muench A, Teichmann D
… +35 more, Kuzman P, Suwala AK, Ippen FM, Müther M, Weber KJ, Wenger-Alakmeh K, Onken J, Vajkoczy P, Behling F, May SA, Ntoulias G, Krauss JK, Atallah O, Esmaeilzadeh M, Mueller WC, Heppner FL, Radbruch H, Dittmayer C, Stenzel W, Koch A, Capper D, Kaul D, Paulus W, Plate KH, Steinbach JP, Czabanka M, Beschorner R, von Deimling A, Bockmayr M, Neumann JE, Brandner S, Krieger T, Hartmann C, Thomas C, Schweizer L
Acta Neuropathol
· 2025 Jun · PMID 40498174
·
Full text
Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). C...Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). Currently, the risk of progression is evaluated using atypical features and an elevated Ki67 proliferation index. However, these markers lack consistent definitions, raising the need for objective criteria. Genome-wide DNA methylation profiles were examined in 136 tumors histologically classified as CN. Clinical/histopathological characteristics were assessed in 93/90 cases, and whole-exome sequencing was conducted in 12 cases. Clinical and molecular characteristics were integrated into a survival model to predict progression-free survival (PFS). A diagnosis of CN was epigenetically confirmed in 125 of 136 cases (92%). No DNA methylation subgroups were identified, but global DNA hypomethylation emerged as a hallmark feature of CN associated with higher recurrence risk. Risk stratification based on histological features of atypia and Ki67 proliferation index was not reproducible across neuropathologists. Hypomethylation at the FGFR3 locus, accompanied by increased FGFR3 protein expression, was observed in 97% of cases. Gross total resection was associated with significantly improved PFS compared to STR, while patients undergoing STR receiving radiotherapy had a better outcome (p = 0.0001). Younger patients were identified as having a higher risk of recurrence (p = 0.026). Patient age and treatment strategy were key factors associated with survival outcomes in this cohort. These findings underscore the importance of closer follow-up for younger patients and radiotherapy for STR cases. Furthermore, FGFR3 represents a hallmark feature and potential therapeutic target, warranting further investigation.
Broekaart DWM, Sharma A, Ramakrishnan A
… +12 more, Chongtham A, Günther DM, Subramaniyan S, Wang M, Patel V, Zhang B, Grinberg LT, Blitzer RD, Schmidt EF, Shen L, Hof PR, Pereira AC
Acta Neuropathol
· 2025 Jun · PMID 40481857
·
Full text
Tauopathies are characterized by the aggregation and accumulation of hyperphosphorylated tau proteins that correlates with cognitive impairment in affected individuals. The presence of tauopathy follows a temporospatial...Tauopathies are characterized by the aggregation and accumulation of hyperphosphorylated tau proteins that correlates with cognitive impairment in affected individuals. The presence of tauopathy follows a temporospatial spreading pattern in which certain neuronal cell types in specific brain regions are more vulnerable to tau accumulation and atrophy. However, the mechanisms underlying the selective vulnerability of these neurons and regions to pathological tau accumulation are not fully understood. Here, we characterized the presence of phosphorylated tau in excitatory and inhibitory neurons in post-mortem prefrontal cortex of tauopathy patients, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal lobar dementia due to a MAPT mutation. We observed that neuronal tau accumulation across these tauopathies occurs predominantly in excitatory neurons compared to inhibitory neurons. Next, we performed viral translating ribosome affinity purification (vTRAP) from vulnerable and resistant brain regions on vGLUT1 and GAD2 PS19 mice to understand molecular signatures of tau vulnerability. We observed that both vulnerable regions and vulnerable neurons are characterized by alterations in synaptic transmission and neuronal excitability. Transcription factor Mef2c (myocyte enhancer factor 2c) was identified as an upstream regulator affecting myelination and synaptic organization in vulnerable brain regions in PS19 mice. The relevance of these findings was validated in human tauopathies via coexpression network analysis. Concordantly, we observed tau-induced changes in spontaneous postsynaptic currents of excitatory neurons in mice especially in the prefrontal cortex. Taken together, we conclude that selective vulnerability to tau could arise from changes in neurotransmission and synaptic compositions, potentially due to an altered Mef2c transcriptional network.
Faura J, Heeman B, Pottier C
… +25 more, Baker MC, DeJesus-Hernandez M, Küçükali F, Heiß L, Wynants S, Van den Broeck M, De Rijk P, De Pooter T, Joris G, Finch NA, Asmann Y, Strazisar M, Murray ME, Petrucelli L, Oskarsson B, Sleegers K, Josephs KA, Nguyen AT, Reichard RR, Petersen RC, Boeve BF, Graff-Radford NR, Dickson DW, van Blitterswijk M, Rademakers R
Acta Neuropathol
· 2025 Jun · PMID 40478310
·
Full text
Dysregulation of TDP-43 as seen in TDP-43 proteinopathies leads to specific RNA splicing dysfunction. While discovery studies have explored novel TDP-43-driven splicing events in induced pluripotent stem cell (iPSC)-deri...Dysregulation of TDP-43 as seen in TDP-43 proteinopathies leads to specific RNA splicing dysfunction. While discovery studies have explored novel TDP-43-driven splicing events in induced pluripotent stem cell (iPSC)-derived neurons and TDP-43 negative neuronal nuclei, transcriptome-wide investigations in frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP) brains remain unexplored. Such studies hold promise for identifying widespread novel and relevant splicing alterations in FTLD-TDP patient brains. We conducted the largest differential splicing analysis (DSA) using bulk short-read RNAseq data from frontal cortex (FCX) tissue of 127 FTLD-TDP (A, B, C, GRN and C9orf72 carriers) and 22 control subjects (Mayo Clinic Brain Bank), using Leafcutter. In addition, long-read bulk cDNA sequencing data were generated from FCX of 9 FTLD-TDP and 7 controls and human TARDBP wildtype and knock-down iPSC-derived neurons. Publicly available RNAseq data (MayoRNAseq, MSBB and ROSMAP studies) from Alzheimer's disease patients (AD) was also analyzed. Our DSA revealed extensive splicing alterations in FTLD-TDP patients with 1881 differentially spliced events, in 892 unique genes. When evaluating differences between FTLD-TDP subtypes, we found that C9orf72 repeat expansion carriers carried the most splicing alterations after accounting for differences in cell-type proportions. Focusing on cryptic splicing events, we identified STMN2 and ARHGAP32 as genes with the most abundant and differentially expressed cryptic exons between FTLD-TDP patients and controls in the brain, and we uncovered a set of 17 cryptic events consistently observed across studies, highlighting their potential relevance as biomarkers for TDP-43 proteinopathies. We also identified 16 cryptic events shared between FTLD-TDP and AD brains, suggesting potential common splicing dysregulation pathways in neurodegenerative diseases. Overall, this study provides a comprehensive map of splicing alterations in FTLD-TDP brains, revealing subtype-specific differences and identifying promising candidates for biomarker development and potential common pathogenic mechanisms between FTLD-TDP and AD.
Acta Neuropathol
· 2025 Jun · PMID 40465013
·
Full text
Progressive supranuclear palsy (PSP) is mainly a sporadic disease. It has a multifactorial etiology and an interaction between environmental and genetic factors causes disease. While elucidation of environmental risks fo...Progressive supranuclear palsy (PSP) is mainly a sporadic disease. It has a multifactorial etiology and an interaction between environmental and genetic factors causes disease. While elucidation of environmental risks for PSP is still in its infancy, much has been learned about the genetic etiological component of PSP during the past few years. This article reviews genes that convey risk for PSP. All genes have been identified in association studies. Only those genes with the standard threshold for genome-wide significance of P < 5E-8 are covered. These genes include MAPT, KANSL1, PLEKHM1, STX6, MOBP, EIF2AK3, SLC01 A2, DUSP10, APOE, RUNX2, TRIM11, NFASC/CNTN2 and LRRK2. The physiologic function of these genes is described and their potential role in the etiology of PSP is discussed.
Chen CD, Franklin EE, Li Y
… +47 more, Joseph-Mathurin N, Burns AL, Hobbs DA, McCullough AA, Schultz SA, Xiong C, Wang G, Masellis M, Hsiung GR, Gauthier S, Berman SB, Roberson ED, Honig LS, Clarnette R, Ringman JM, Galvin JE, Brooks W, Suzuki K, Black S, Levin J, Aggarwal NT, Jucker M, Frosch MP, Kofler JK, White C, Keene CD, Chen J, Daniels A, Gordon BA, Ibanez L, Karch CM, Llibre-Guerra J, McDade E, Morris JC, Supnet-Bell C, Allegri RF, Lee JH, Day GS, Lopera F, Roh JH, Schofield PR, Mills S, Benzinger TLS, Bateman RJ, Perrin RJ, DIAN-TU Study Team, DIAN-Obs Study Team
Acta Neuropathol
· 2025 Jun · PMID 40459787
·
Full text
Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40....Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits-and on potentially myriad 'downstream' pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases-gantenerumab (n = 4), solanezumab (n = 4), placebo/no treatment (n = 2)-and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle 'downstream' effects.
Ondrejcak T, Hu NW, Coode E
… +8 more, Campbell T, Corbett GT, Doykov I, Mills K, Walsh DM, Livesey FJ, Rowan MJ, Klyubin I
Acta Neuropathol
· 2025 Jun · PMID 40455293
·
Full text
Immunotherapies targeting extracellular tau share the premise that interrupting cell-to-cell spread of tau pathology in Alzheimer's disease (AD) will slow dementia pathogenesis. Whether these interventions affect the act...Immunotherapies targeting extracellular tau share the premise that interrupting cell-to-cell spread of tau pathology in Alzheimer's disease (AD) will slow dementia pathogenesis. Whether these interventions affect the actions of synaptotoxic, extracellular tau species that may contribute to cognitive impairment is relatively unknown. Here, we assayed synaptic plasticity disruption in anaesthetised live rats caused by intracerebral injection of synaptotoxic tau present either in (a) secretomes of induced pluripotent stem cell-derived neurons (iNs) from people with Trisomy 21, the most common genetic cause of AD, or (b) aqueous extracts of human AD brain. Extracellular tau in iN secretomes was found to include fragments that contain the extended microtubule-binding regions of tau, MTBR/R' and adjacent C-terminal sequences. Immunodepletion or co-injection with antibodies targeting epitopes within these fragments prevented the acute disruption of synaptic plasticity by these patient-derived synaptotoxic tau preparations. Moreover, a recombinant human tau fragment encompassing the core MTBR/R'-region present in tau fibrils, tau, potently mimicked the deleterious action of patient-derived tau. MTBR/R'-directed antibodies also rapidly reversed a very persistent synaptotoxic effect of soluble brain tau. Our findings reveal a hitherto relatively unexplored potential benefit of targeting extracellular MTBR/R' tau on correcting synaptic dysfunction.
Liao F, Calvo-Rodriguez M, Chhaya M
… +14 more, Sefrin JP, Charych EI, Mezler M, Clausznitzer D, McGlame EJ, Zhao K, Rodgers A, Cao Y, Secker PF, Fernandez Garcia-Agudo L, Huang L, Klein C, Dellovade T, Karran E
Acta Neuropathol
· 2025 Jun · PMID 40455292
·
Full text
Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by...Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (Aβ). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant Aβ fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. In vivo two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.
Lioudyno MI, Sevrioukov EA, Olivarria GM
… +12 more, Hitchcock L, Javonillo DI, Campos SM, Rivera I, Wright ST, Head E, Fortea J, Wisniewski T, Cuello AC, Do Carmo S, Lane TE, Busciglio J
Acta Neuropathol
· 2025 May · PMID 40445428
·
Full text
Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility...Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e.g., TMPRSS2) or indirectly influence the SARS-CoV-2 entry into central nervous system (CNS) cells. The anti-viral immune response may also be altered in cells with trisomy-21 (T21) due to triplication of genes encoding for several interferon receptor subunits and interferon-stimulated genes (ISGs). Here, we demonstrate that human cells derived from fetal cortical specimens and maintained in primary cultures are susceptible to infection with a molecular clone of vesicular stomatitis virus engineered to express the Spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and to authentic SARS-CoV-2. The level of SARS-CoV-2 infectivity in cultures originated from different cortical specimens varied, seemingly depending on ploidy and chromosomal sex of the cells. We confirmed the presence of ACE2 and TMPRSS2 in cultures and found that XY T21 group had the highest TMPRSS2 mRNA levels, which was associated with increased infectivity in XY-compared to XX T21 cultures. The XX T21 cultures exhibited elevated expression of several ISGs (MX1, STAT1, and STAT2) which was associated with lower infectivity. The comparisons of postmortem aged brain specimens revealed reduced ACE2, TMPRSS2, but elevated STAT2 protein levels in individuals with DS and Alzheimer's disease (DS-AD) compared to control and Alzheimer's disease (AD) group. Collectively, these results suggest multifactorial regulation of SARS-CoV-2 infectivity in cortical cells that involves ploidy, chromosomal sex, and the expression of genes implicated in regulation of virus entry and anti-viral response as contributing factors.
Smith LA, Olkhova EA, Lax NZ
… +5 more, Ng YS, Taylor RW, Gorman GS, Erskine D, McFarland R
Acta Neuropathol
· 2025 May · PMID 40445405
·
Full text
Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neur...Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort (n = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5-39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.
Rodriguez-Mogeda C, Koubiyr I, Prouskas SE
… +12 more, Georgallidou M, van der Pol SMA, Fernandez RF, de Graaf YG, van der Werf YD, Jonkman LE, Schenk GJ, Barkhof F, Hulst HE, Witte ME, Schoonheim MM, de Vries HE
Acta Neuropathol
· 2025 May · PMID 40434526
·
Full text
Thalamic atrophy already occurs in the early stages of multiple sclerosis (MS) and continues progressively throughout the disease. Demyelination is one of the main pathological hallmarks of MS and yet, thalamic demyelina...Thalamic atrophy already occurs in the early stages of multiple sclerosis (MS) and continues progressively throughout the disease. Demyelination is one of the main pathological hallmarks of MS and yet, thalamic demyelination does not correlate well with thalamic atrophy. By combining post-mortem magnetic resonance imaging with immunohistochemistry of thalami from 13 control and 13 MS donors, we investigated the underlying pathological contributors of thalamic atrophy and pathology. We first assessed the volumes of four thalamic nuclei groups (anterior, lateral, medial and posterior). Then, diffusion weighted imaging was used to assess the microstructural integrity of white matter tracts connecting each thalamic nuclei group. In addition, we studied myelination, inflammation, neurodegeneration and microglial activation by immunohistochemistry. We uncovered that medial and posterior thalamic nuclei were more atrophic compared to the anterior and lateral nuclei. Bilateral posterior nuclei and the right medial and anterior nuclei showed reduced fractional anisotropy in connected white matter tracks. We further show that microglial cells in the mediodorsal nuclei have an increased density and morphological complexity in MS compared to control donors. Microglia show signs of phagocytosis of pre-synapses, although we did not observe an overall synaptic loss in the thalamus of MS donors. These microglial changes within mediodorsal nuclei correlated with lower medial thalamic volume. Taken together, this study provides evidence that thalamic (subnuclear) atrophy relates tostructural thalamic network disconnection and within-thalamic microglial changes, but not thalamic demyelination. These findings could impact future treatment strategies aimed at thalamic neuroprotection.
Acta Neuropathol
· 2025 May · PMID 40411591
·
Full text
In Alzheimer's disease, accumulation of amyloid-β (Aβ) peptide is thought to cause formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, which correlates with neuronal loss and cognitive impai...In Alzheimer's disease, accumulation of amyloid-β (Aβ) peptide is thought to cause formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, which correlates with neuronal loss and cognitive impairment, but the mechanism linking Aβ and tau pathologies is unknown. Dystrophic neurites, which surround Aβ plaques and accumulate phosphorylated tau and other proteins, may play a role in seeding and spreading of pathologic tau. Here, we investigate the novel hypothesis that improved membrane repair capacity decreases dystrophic neurite formation by protecting axons from Aβ-induced membrane damage. Using a ratiometric calcium sensor and a FRET-based calpain cleavage sensor, we demonstrate that dystrophic neurites in 5XFAD mice have elevated resting calcium levels and calpain activity because of putative membrane damage. Annexin A6, a plasma membrane repair in muscle and neurons, is present at plasma membrane of neurons and dystrophic neurites in murine and human brains. Overexpression of annexin A6 in brains of 5XFAD mice decreased size and quantity of dystrophic neurites and accumulation of phospho-tau181, an early biomarker of amyloid pathology. Phospho-tau231, another early amyloid biomarker, and phosphorylated of tau kinases, c-jun N-terminal kinase (JNK) and Calmodulin Kinase II (CaMKII) accumulate in dystrophic neurites in the brains of amyloid pathology mice and humans with AD, suggesting that dystrophic neurites are sites of active tau phosphorylation. Overexpression of dominant-negative annexin A6 in 5XFAD mice increased dystrophic neurites and phospho-tau181. Intracerebral injection of recombinant annexin A6 in 5XFAD and APP-NLGF knock-in mice resulted in localization of recombinant A6 to membranes of dystrophic neurites, suggesting therapeutic potential of recombinant annexin A6 for AD. In conclusion, dystrophic neurites have Aβ-induced membrane damage characterized by calcium elevation, calpain activation, and accumulation of tau kinases and phosphorylated tau. Overexpression of annexin A6 reduces dystrophic neurites and phospho-tau accumulation, suggesting that annexin A6-mediated membrane repair may represent a novel therapeutic approach for AD.
Braak H, Mayer B, Feldengut S
… +2 more, Schön M, Del Tredici K
Acta Neuropathol
· 2025 May · PMID 40407905
·
Full text
Sporadic Alzheimer's disease (AD) involves specific neuronal types and progresses in a systematic manner, permitting subdivision into six neuropathological stages. Neurofibrillary tangle (NFT) stages I-III display abnorm...Sporadic Alzheimer's disease (AD) involves specific neuronal types and progresses in a systematic manner, permitting subdivision into six neuropathological stages. Neurofibrillary tangle (NFT) stages I-III display abnormal tau inclusions confined to subcortical nuclei and temporal allocortical regions, frequently without amyloid β (Aβ) deposition. We previously suggested a sequence of neuronal involvement in AD that could proceed from entorhinal pre-α cells to hippocampal prosubicular pyramidal cells and the CA1/CA2 sectors, from there to the thorny excrescences on mossy cells in CA3/CA4, and, finally, from the mossy cells to dentate fascia (Fd) granular cells. Here, we aimed to see if associations existed between the early NFT stages I-III, when Aβ deposits are frequently absent, and the following four categories: (1) anatomical regions and abnormal morphological tau changes in region-specific layers, (2) nerve cell loss, (3) APOE genotype, and (4) the trajectory (directionality) of tau progression in the hippocampal formation. To do so, we examined the transentorhinal/entorhinal regions and hippocampal formation using AT8-immunohistochemistry in 100 µm sections from N = 308 brains with tau inclusions lacking Aβ deposits between NFT stages I and III (average age at death 66.7 years for females, 66.4 years for males). Our results indicated a significantly (p < 0.001) ordered progression of abnormal tau in a direction opposite to currently known unidirectional intrahippocampal connections, thereby indirectly supporting the idea of transneuronal abnormal tau spreading, i.e., anterogradely, through the hippocampal formation. Tau-related neuronal loss was also significant (p < 0.001 for the transentorhinal/entorhinal regions and for sectors CA1/CA2 and p = 0.003 for CA3/CA4/Fd). These findings challenge the amyloid cascade and the PART hypotheses, corroborating the concept that early AD-related tau inclusions and tau-related neuronal loss occur independently of Aβ deposition.
Farrell C, Buhidma Y, Mumford P
… +13 more, Heywood WE, Hällqvist J, Flores-Aguilar L, Andrews EJ, Rahimzadah N, Taso OS, Doran E, Swarup V, Head E, Lashley T, Mills K, Toomey CE, Wiseman FK
Acta Neuropathol
· 2025 May · PMID 40387921
·
Full text
Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer's disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimer's d...Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer's disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimer's disease (DSAD) to demographically matched cases of early onset AD and healthy ageing controls. We find dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD. To understand the cell types that may contribute to changes in protein abundance, we undertook a matched single-nuclei RNA-sequencing study, which demonstrated that APOE expression was elevated in subtypes of astrocytes, endothelial cells, and pericytes in DSAD. We further investigate how trisomy 21 may cause increased APOE. Increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people with DSAD, altering disease mechanisms with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people with DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this vulnerable group of individuals who have high risk of early onset dementia.
Tau seeding and propagation are defining features of all tauopathies, including Alzheimer's disease, but the underlying molecular drivers remain incompletely understood. Here, we reveal that Fyn expression boosts massive...Tau seeding and propagation are defining features of all tauopathies, including Alzheimer's disease, but the underlying molecular drivers remain incompletely understood. Here, we reveal that Fyn expression boosts massive Tau pathology in the mouse brain and enhances Tau seeding induced by pathological Tau seeds in biosensor cells. However, even in the absence of seeds, Fyn itself, via its palmitoylation, triggers the de novo formation of small, plasma membrane-anchored Tau microclusters, which initiate pronounced and diverse intra- and transcellular Tau seeding in vitro and in vivo. Mechanistically, membrane-associated Fyn phosphorylates Tau at its Tyr310 epitope and then recruits and activates GSK3β locally, which further phosphorylates Tau at Ser/Thr sites in the microclusters, eliciting their full seeding capacity. Our data suggest that Fyn not only serves as a master switch that initiates Tau pathogenesis on its own, but also augments a pre-existing Tau pathology, leading to a vicious cycle of Tau aggregation.