Flores-Aguilar L, Zaikos TD, Rivera I
… +29 more, Wright ST, Lou J, Gawronski B, Gonzalez L, Berry JV, Rouanet J, Edwards NC, Hoang DK, Wood K, Granholm AC, Mufson EJ, Monuki ES, Ikonomovic MD, Kofler J, Doran EW, Lott IT, Totoiu MO, Hom CL, Lai F, Yong WH, Schmitt FA, Harp J, Nelson PT, Gutierrez J, Lao PJ, Wilcock DM, Brickman AM, Head E, Alzheimer’s Biomarker Consortium-Down syndrome (ABC-DS)
Acta Neuropathol
· 2026 May · PMID 42141233
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Individuals with Down syndrome (DS) develop Alzheimer's disease neuropathological change (ADNC) by the age of 40 years, and most develop dementia by their early 50s. The frequency of co-pathologies in clinically and neur...Individuals with Down syndrome (DS) develop Alzheimer's disease neuropathological change (ADNC) by the age of 40 years, and most develop dementia by their early 50s. The frequency of co-pathologies in clinically and neuropathologically characterized adults with DS has not been systematically characterized. We characterized the frequency of ADNC and common co-pathologies, including cerebral amyloid angiopathy (CAA), Lewy pathology (LP), limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), hippocampal sclerosis (HS), and other cerebrovascular and macroscopic findings reported in standardized National Alzheimer's Coordinating Center (NACC) neuropathology forms in 63 adults with DS over 40 years. A secondary exploratory objective was to compare the neuropathological profiles between individuals with (n = 55) and without (n = 8) dementia from the same autopsy cohort. In the full autopsy cohort, cortical and hippocampal atrophy, and moderate-to-severe locus coeruleus hypopigmentation was a common finding. Pure ADNC, was present in only 29% of individuals. CAA was the most frequent co-pathology, present in approximately 84% of individuals followed by LP (21%), HS (19%), and LATE-NC (17%). Atherosclerosis and arteriolosclerosis were infrequent. In exploratory comparisons between dementia groups, brain weight was significantly lower in individuals with dementia than in those without (900 ± 116 vs 1060 ± 108 g P = .0006), and severe hippocampal atrophy and locus coeruleus hypopigmentation were more frequent in those with dementia (P = .049, P = .009, respectively). Advanced Braak NFT stage, frequent neuritic plaques, and high ADNC were more frequent in individuals with dementia (P = .0001, P = .03, P = .0016, respectively). LATE-NC and HS occurred exclusively in individuals with dementia, while LP and CAA were found in both groups. Individuals without dementia showed a less complex co-pathology profile than those with dementia. Our findings demonstrate that co-pathologies are present in people with DS, and that despite their genetic predisposition to AD, some individuals with DS may exhibit resilience and resistance mechanisms to AD.
Hatano Y, Nakahara A, Tada M
… +3 more, Kakita A, Onodera O, Ishihara T
Acta Neuropathol
· 2026 May · PMID 42141160
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patien...Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E (APOE) ε4 is known to influence the spread of pathological protein in several neurodegenerative diseases, raising the possibility that it also modulates the pathological distribution of TDP-43 inclusions in ALS. We investigated this hypothesis in a cohort of 145 autopsy-confirmed sporadic ALS cases. ALS-associated TDP-43 pathology was classified into two subtypes: type 1 - largely restricted to motor regions - and type 2 - characterized by widespread cortical involvement. APOE genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-β and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among APOE ε4, temporal clinical parameters, Alzheimer's disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model. APOE ε4 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE ε4 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-β and tau pathology, while also reproducing the canonical cascade linking APOE ε4 to amyloid-β and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that APOE ε4 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer's disease pathology. Incorporation of APOE genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.
Wu L, Akingbade T, Nelson PT
… +2 more, Wang SJ, Xu B
Acta Neuropathol
· 2026 May · PMID 42141120
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Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative disease marked by TDP-43 proteinopathy, affecting approximately one-third of individuals aged 80 and above. LATE neuropathological change...Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative disease marked by TDP-43 proteinopathy, affecting approximately one-third of individuals aged 80 and above. LATE neuropathological change (LATE-NC) is characterized by the accumulation of phosphorylated TDP-43 preferentially in the limbic system, with potential extension to the neocortex and other brain regions. Notably, the anatomic pattern of LATE-NC differs from that seen in frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP). LATE-NC can occur in a "pure" form but more commonly exists alongside other dementia-related comorbidities, including both degenerative and vascular pathologies. When those "mixed" pathologies are factored in, LATE contributes significantly to cognitive decline in human populations. However, LATE currently lacks a molecular-specific diagnostic method for definitive diagnosis in living people. There are new consensus-based guidelines for predicting the presence of either pure LATE-NC or LATE-NC combined with Alzheimer's disease neuropathologic change (ADNC). Aimed at developing more specific diagnostic methods, recent research efforts have been directed toward identifying unique features on neuroimaging and molecular signatures in biological fluids such as blood and cerebrospinal fluid to facilitate clinical diagnosis for LATE. This review discusses current progress in molecular understanding of LATE-NC, the search for biomarkers for LATE, and highlights key gaps that need to be addressed to advance early detection and improve patient management and clinical trial stratification.
Kaya ZB, Amerna D, Susarla A
… +8 more, Lim MJ, Bregendahl M, Sekiya H, DeTure M, Ross OA, Dickson DW, Boschen SL, McLean PJ
Acta Neuropathol
· 2026 May · PMID 42118167
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Parkinson's disease (PD) is neuropathologically characterized by the abnormal accumulation of fibrillar alpha-synuclein (aSyn) within selectively vulnerable neuronal populations. Although this pathological hallmark is sh...Parkinson's disease (PD) is neuropathologically characterized by the abnormal accumulation of fibrillar alpha-synuclein (aSyn) within selectively vulnerable neuronal populations. Although this pathological hallmark is shared across individuals with PD, the disease presents with marked clinical heterogeneity in age of onset, progression rate, and clinical symptoms, the molecular basis of which remains incompletely understood. In this study, we examined whether biochemical and seeding-related properties of aSyn vary across clinically defined PD subgroups. Using well-characterized, autopsy-confirmed PD cases and matched controls we applied complementary biochemical, cell-based aggregation, and cell-free seed amplification assays (SAA) to investigate aSyn molecular heterogeneity and its potential contribution to disease diversity. Autopsy-confirmed PD cases were classified as early-onset (< 60 years) or late-onset (> 60 years), with the late-onset group further subdivided into fast-progressing (< 5 years duration) and slow-progressing (> 10 years duration). Analysis of detergent-insoluble fractions from PD brains revealed significantly elevated pSer129-aSyn levels compared to controls, while total aSyn was highest in late-onset PD. Seeding bioactivity measured via FRET-based biosensor cells was significantly increased in PD, albeit with substantial inter-individual variability; late-onset and slow-progressing groups exhibited the strongest activity. Seeding activity correlated positively with pSer129-aSyn levels. These findings were supported by high-content imaging, which demonstrated increased intracellular aggregate burden in PD samples. SAA confirmed robust seeding activity in PD, with shorter lag times relative to controls. Finally, proteinase K digestion of amplified products revealed differences in proteolytic resistance between PD and control samples, consistent with biochemical heterogeneity of seeding-competent species. Collectively, these findings suggest that aSyn pathology in PD is associated with marked inter-individual variability in biochemical and seeding properties. Our results highlight the importance of considering molecular heterogeneity at the individual patient level when investigating PD pathobiology and supports the need for precision medicine approaches for PD patients.
Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organella...Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and assemble a reference neuroanatomical atlas of lipofuscin accumulation with age and NCL (Type 1; CLN1) progression across 425 fine brain regions. We identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology via multimodal mass spectrometry, ultrastructural analyses, and assays of cellular and enzymatic metabolism. We find the protein and lipid composition of lipofuscin in the aged and CLN1 brain to be remarkably similar. Dissection of implicated molecular pathways reveals protein S-acylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and CLN1. Notably, > 95% of lipofuscin resident proteins can be S-acylated and many are substrates of the enzyme PPT1, validating a seminal hypothesis that CLN1 lipofuscin contains these lipid-modified proteins. Further, we discover deficient de-S-acylation is correlated with lipofuscin load in healthy aging, as the specific de-S-acylation enzyme activity of PPT1 is found to decline with advancing age. Finally, we identify lipid metabolite biomarkers of lipofuscin, including long-chain polyunsaturated fatty acids, bis(monoacylglycerol)phosphate (BMP), and oxidized phosphatidylethanolamine (OxPE) lipid species. Overall, we provide a comprehensive redefinition of lipofuscin neuropathology and a resource for studying aging, lysosomal storage disorders, and neurodegeneration.
Robinson JL, Cai H, Loh NJ
… +12 more, Vazquez O, Khodakaramimaghsoud Z, Suh E, Van Deerlin VM, Yushkevich PA, Mechanic-Hamilton D, Xie SX, Ohm DT, Wolk DA, Irwin DJ, Phillips JS, Lee EB
Acta Neuropathol
· 2026 May · PMID 42069798
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Neurofibrillary tangles in Alzheimer's disease (AD) stereotypically spread from the medial temporal lobe to association areas and then to idiotypic areas (i.e., primary motor, somatosensory, auditory, and visual). Previo...Neurofibrillary tangles in Alzheimer's disease (AD) stereotypically spread from the medial temporal lobe to association areas and then to idiotypic areas (i.e., primary motor, somatosensory, auditory, and visual). Previous studies have reported variable and clinically relevant tangle densities across the hippocampus and association cortices, but the idiotypic tangle burden is understudied. In this study, we measured tangle density using immunohistochemistry in three idiotypic cortices (primary motor, somatosensory, and visual), three association cortices (middle frontal, superior temporal, and inferior parietal), and two hippocampal sectors (CA1 and subiculum) in 144 cases with a high level of AD neuropathologic change. Clinical diagnoses included late-onset AD (LOAD, n = 50), early-onset AD (EOAD, n = 21), behavioral variant frontotemporal dementia (bvFTD, n = 19), corticobasal syndrome (CBS, n = 18), logopenic primary progressive aphasia (lvPPA, n = 21), and posterior cortical atrophy (PCA, n = 15). We algorithmically assigned cases outside the interquartile ranges of mean tangle ratios of association:hippocampal, idiotypic:association, and idiotypic:hippocampal to mutually exclusive subtypes: idiotypic-susceptible, associative-predominant, limbic-predominant, or typical Braak (for all remaining cases). Regional tangle burdens differentiated subtypes, while female sex, younger ages, and longer disease durations also influenced tangle severity. Compared to typical Braak cases, idiotypic-susceptible and associative-predominant cases exhibited shorter disease duration and younger age at death while limbic-predominant cases were older. The MAPT H1H1 haplotype also differed by subtype, being most prevalent in limbic-predominant and least common in idiotypic-susceptible and associative-predominant subtypes. Clinically, the idiotypic-susceptible subtype associated with CBS (56%), the associative-predominant subtype with bvFTD (53%), and the limbic-predominant subtype with LOAD (14%). The typical Braak subtype characterized 74-76% of amnestic AD cases and 32-53% of non-amnestic AD cases. Moreover, k-means clustering corroborated four clusters including the idiotypic-susceptible and associative-predominant patterns. Our results confirm previously described tau subtypes and describe an idiotypic-predominant subtype with clinical relevance and distinct demographic and genetic characteristics in AD.
Mignolet M, Deroux C, Florkin T
… +15 more, Bielarz V, De Swert K, Halloin N, Sprimont L, Ladang A, George F, Gilloteaux J, Abeloos L, Garin P, Van Weyenbergh J, Jamoulle M, Diederich C, Gillet NA, Bulpa P, Nicaise C
Acta Neuropathol
· 2026 Apr · PMID 42053865
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Approximately 30% of long COVID patients still experience neurological symptoms (brain fog, pain, chronic fatigue) more than 4 months after the onset of COVID-19. This condition, known as 'neurological long COVID', remai...Approximately 30% of long COVID patients still experience neurological symptoms (brain fog, pain, chronic fatigue) more than 4 months after the onset of COVID-19. This condition, known as 'neurological long COVID', remains poorly understood and might be explained by a persisting autoimmune response against nervous-derived self-antigens. The aim of this study is to determine whether IgG autoantibodies from long COVID patients with neurological sequelae can bind to central or peripheral nervous system epitopes and trigger neuropsychiatric symptoms upon passive transfer into mice, thereby mirroring patient-reported manifestations. Long COVID patients meeting the 2021 consensus WHO definition were included following a standardized neuropsychological assessment, while excluding patients with a medical history of autoimmune and neurological disorders. Age- and sex-matched asymptomatic individuals were used as healthy controls. Total IgGs were isolated using protein G purification and injected intraperitoneally into C57Bl6/J mice for four consecutive days. During the two weeks post-injections, behavioral tests assessed mechanical allodynia, thermal hyperalgesia, spatial working memory, depression, and anxiety. Mice injected with IgG from long COVID patients showed no difference with the control group in terms of anxiety or depression behaviors, short- or long-term spatial memories. However, they displayed a transient decrease of paw withdrawal threshold and thermal hypersensitivity during the first week. This effect was abolished when IgG-depleted serum or papain-digested IgGs were transferred. IgG from long COVID patients accumulated in the lumbar dorsal root ganglia of injected mice and colocalized with proprioceptive and nociceptive sensory neurons, without inducing local neuroinflammation or astrogliosis. When applied onto human post-mortem DRG tissue, patient-derived IgG also exhibited immunoaffinity for sensory neuron somata. These data demonstrate that IgGs from long COVID patients bind to peripheral sensory neurons and induce pain-related symptoms in mice. Our findings also support the hypothesis that autoantibodies mediate pain-related pathophysiology in the spectrum of long COVID symptoms.
Disease progression in multiple sclerosis (MS) remains a major unmet clinical challenge, as it is driven by pathogenic mechanisms that are poorly targeted by currently available disease-modifying treatments. Whereas acut...Disease progression in multiple sclerosis (MS) remains a major unmet clinical challenge, as it is driven by pathogenic mechanisms that are poorly targeted by currently available disease-modifying treatments. Whereas acute focal inflammation characterizes the relapsing-remitting phase, converging neuropathological, imaging and experimental evidence identifies a chronic low-grade compartmentalized inflammatory process, the so-called "smoldering" inflammation, as a central driver of disease progression in MS. Recent findings suggest that both tissue hypoxia (primarily resulting from vascular dysfunction) and virtual hypoxia (a state of metabolic supply-demand mismatch culminating in bioenergetic failure) may critically contribute to the onset, persistence and compartmentalization of smoldering inflammation. In this review, we first delineate the pathological mechanisms underlying smoldering inflammation, distinguishing between lesional and extra-lesional features. We then examine the processes leading to tissue and virtual hypoxia in MS. As a key link between smoldering inflammation and hypoxia, we focused on the Hypoxia-Inducible Factor (HIF) signaling, the master regulator of cellular responses to hypoxia. Particularly, we reviewed recent evidence supporting its role as a central immunometabolic hub shaping immune and glial cell function within the hypoxic microenvironment of smoldering inflammation in MS. Finally, we critically evaluate the potential of the HIF signaling as a therapeutic target to hamper smoldering inflammation and disease progression in MS.
Yuen M, Zhang K, Marchant RG
… +23 more, Ishimura R, Graham M, Aung-Htut M, Bryen S, Rius R, Marshall L, Aryamanesh N, Dziaduch G, Joshi H, Weisburd B, Wilton SD, Wilson M, Gear R, Hennington L, Lau S, Doyle H, Krivanek M, Leventer RJ, White SM, Sandaradura SA, Komatsu M, Evesson FJ, Cooper ST
Acta Neuropathol
· 2026 Apr · PMID 42045457
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We investigated the pathogenicity of a homozygous intronic variant in CDK5RAP3, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. CDK5RAP3 variants have...We investigated the pathogenicity of a homozygous intronic variant in CDK5RAP3, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. CDK5RAP3 variants have not been linked to human disorders to date; however, murine Cdk5rap3 knockout is embryonic lethal and variants in five other UFMylation components cause severe neurodevelopmental conditions. A segregating homozygous variant, chr17(GRCh38):g.47974691G > A, CDK5RAP3 NM_176096.3:c.334 + 243G > A, was identified by trio whole-genome and proband RNA sequencing in Family A and by trio whole-exome sequencing data reanalysis in Family B. Variant pathogenicity investigations included RT-PCR, Western blot, co-immunoprecipitation and (phospho)proteomics to assess transcript, protein and UFMylation complex effects. Antisense oligonucleotide-mediated rescue of CDK5RAP3 expression combined with proteomics and phosphoproteomics defined the mechanistic impact of CDK5RAP3 deficiency and rescue in amniocytes from an affected individual. All three affected individuals showed foetal growth restriction, foetal akinesia, pontocerebellar hypoplasia, arthrogryposis and hepatic pathology. CDK5RAP3 c.334 + 243G > A activates a cryptic donor splice-site causing pseudoexon/intron inclusion triggering nonsense-mediated decay and deficiency of full-length CDK5RAP3 (NP_788276.1), while potentially allowing retained expression of C-terminal alternative isoforms. Co-immunoprecipitation revealed only full-length CDK5RAP3 binds UFL1, whereas C-terminal isoforms cannot. Primary amniocytes showed CDK5RAP3 deficiency was associated with impaired UFMylation of known substrates, RPL26 and UFBP1. Proteomic and phosphoproteomic analyses revealed dysregulation of extracellular matrix organisation, cell adhesion, mitotic/genome stability pathways, cytoskeletal networks and neuronal guidance, which were reversed by restoration of canonical CDK5RAP3 expression via splice-correcting antisense oligonucleotides. Phosphoproteomic data implicate CDK5RAP3 as an upstream regulator of UFL1 S462 phosphorylation, known to be regulated by Ataxia-telangiectasia mutated (ATM) signalling. Our findings provide strong evidence linking deficiency of full-length CDK5RAP3 to severe neurodevelopmental, liver and muscle dysfunction. This study further highlights the therapeutic potential of ASO-based deep-intronic splicing defect correction.
Rahmanzade R, Schweizer L, Schmid S
… +29 more, Lausová T, Sigismondo G, Esmaeili Benvidi M, Patel R, Kaan AF, Banan R, Reuss D, Jäger N, Forster MT, Zeller V, Kohlhof-Meinecke P, Fisseler-Eckhoff A, Carl B, Harter PN, Lamszus K, Schüller U, Zapotocky M, Acker T, Hanemann CO, Schittenhelm J, Brack E, Flucke U, Mechtersheimer G, Bertero L, Haberler C, Capper D, von Deimling A, Sievers P, Sahm F
Acta Neuropathol
· 2026 Apr · PMID 42034799
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Intracranial sarcomas can arise secondarily from primary brain tumors, including gliomas and meningiomas, either spontaneously or following radiotherapy. The current WHO classification recognizes sarcomatous transformati...Intracranial sarcomas can arise secondarily from primary brain tumors, including gliomas and meningiomas, either spontaneously or following radiotherapy. The current WHO classification recognizes sarcomatous transformation in several tumor entities; however, sarcomas arising from meningiomas remain poorly characterized and are regarded as a possible histological manifestation within the spectrum of anaplastic meningiomas. We analyzed nine matched meningioma-sarcoma pairs using integrated histopathological assessment and molecular profiling, including DNA methylation analysis, next-generation sequencing, copy number profiling, and proteomics. Although recurrent sarcomatous tumors were clonally related to their meningioma precursors-sharing identical NF2 alterations and overlapping chromosomal aberrations-they demonstrated pronounced divergence at the histological, immunophenotypic, and epigenetic levels. Importantly, sarcomatous transformation occurred in four cases without prior radiotherapy. Sarcomatous recurrences exhibited loss of meningothelial markers and acquired expression of cytokeratin and myogenic markers. DNA methylation profiling revealed a shift away from canonical meningioma signatures toward profiles resembling non-meningothelial mesenchymal tumors. Proteomic analysis showed consistent upregulation of SOX2 in sarcomatous tumors compared with their primary counterparts, suggesting acquisition of stem-like features during lineage divergence. Clinically, these tumors were associated with aggressive growth, early recurrence, and extracranial metastases, resembling malignant sarcomas more closely than anaplastic meningiomas. In addition, analysis of an institutional cohort of NF2-mutant intracranial tumors (n = 316) suggests that sarcomas with inactivating NF2 mutations may originate from meningiomas even in the absence of a clinically recognized precursor. Together, these findings suggest that sarcomatous transformation represents a rare evolutionary endpoint in NF2-mutant meningiomas, marked by clonal continuity but pronounced biological divergence. These results highlight limitations of morphology-based classification and emphasize the value of integrated molecular diagnostics in distinguishing these tumors from conventional high-grade meningiomas. Given their sarcoma-like behavior despite a meningioma ancestry, these tumors may not be adequately captured by current meningioma grading schemes.
The anterior cingulate cortex (ACC), crucial for executive function, is frequently impaired in progressive supranuclear palsy (PSP), yet mechanisms underlying this selective vulnerability remain unclear. Given the integr...The anterior cingulate cortex (ACC), crucial for executive function, is frequently impaired in progressive supranuclear palsy (PSP), yet mechanisms underlying this selective vulnerability remain unclear. Given the integration of astrocytes into neural circuits, we hypothesized that astrocyte dysfunction and altered astrocyte-neuron crosstalk contribute to functional abnormalities in the ACC in PSP. To test this hypothesis, we conducted a multimodal analysis integrating SWATH-MS-based proteomics, histopathology, and in vivo magnetic resonance spectroscopy (MRS) in postmortem and living brains of patients with PSP and healthy controls (HCs). The astrocytic markers glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) were significantly elevated in the ACC of patients with PSP compared with those in HCs. Enhanced astrocytic Ca⁺ signaling through the IP3-Ca⁺ cascade was suggested in the ACC of patients with PSP, consistent with elevated myo-inositol levels on MRS. Proteomic data revealed reduced expression of pyruvate dehydrogenase complex components (DLD and PDHX) and oxidative phosphorylation-related proteins, including astrocyte-enriched genes such as ETFDH and UQCRC1. MRS also revealed significantly increased levels of lactate and glutamate in the ACC of patients with PSP compared with those in HCs. Notably, myo-inositol, lactate, and glutamate levels were positively correlated, indicating astrocyte-associated metabolic dysfunction. Expression of glutamate-glutamine cycle-related molecules and neuronal markers was negatively correlated with GFAP and AQP4 levels, suggesting that astrocytic dysfunction is associated with alterations in the excitatory/inhibitory balance in the ACC of patients with PSP. These findings demonstrate that multiple aspects of astrocyte-neuron crosstalk, including AQP4-mediated glymphatic clearance, energy metabolism, and neurotransmitter cycling, are altered in the ACC of patients with PSP. Such disruptions may contribute to neuronal dysfunction. Our study highlights astrocyte dysfunction as a central feature of the PSP pathophysiology.
Hill E, Linehan J, Farmer M
… +13 more, Jakubcova T, Hamdan S, Tomlinson A, Purro S, Argentina F, Jones E, Kaye N, Fitzhugh C, de Silva R, Brandner S, Collinge J, Cunningham TJ, Mead S
Acta Neuropathol
· 2026 Apr · PMID 42017988
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Genetically mediated increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk mechanism for progressive supranuclear palsy and sporadic prion disease. Increase...Genetically mediated increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk mechanism for progressive supranuclear palsy and sporadic prion disease. Increased syntaxin-6 protein levels are also causally associated with Alzheimer's disease, suggesting it may have shared roles across multiple neurodegenerative diseases. However, no study has validated its functional role in tauopathies. To validate a role for syntaxin-6 in tauopathy pathogenesis, we knocked out syntaxin-6 in humanised P301S tauopathy mice. Mice underwent longitudinal rotarod testing, gait analysis, frailty and weight assessment, with neuropathological, biochemical and pathological analyses at 3 and 5 months. Stx6;hTau mice showed motor impairment from 1 month of age, which was partially rescued by syntaxin-6 knockout from months 1 to 4, with additional protection of gait at 5.5 months. Physiologically, syntaxin-6 knockout exerted a protective effect on weight trajectories and measures of frailty. Reduced neurodegeneration in the superficial cortex was observed at 3 months, as well as higher synaptic coverage at 5 months of age, supporting preserved neuropathological measures related to function. We further observed localised increases in tau pathology in the spinal cord and defined brain regions in young Stx6;hTau mice, despite total tau levels being comparable, in keeping with altered trafficking of pathological tau species with syntaxin-6 knockout. Despite a partial, early phenotypic rescue of functional measures, terminal endpoint comparisons were confounded by a 20% weight loss culling rule, as knockout mice maintained higher absolute weight. Taken together, this study functionally validates a role for syntaxin-6 in tauopathy pathogenesis, with syntaxin-6 knockout resulting in an early protective effect on multiple disease-relevant phenotypes in a humanised tauopathy model.
Yuan S, Essepian N, Roberts R
… +4 more, Sherman E, Wang Q, Erisir A, Jiang L
Acta Neuropathol
· 2026 Apr · PMID 42017968
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The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer's disease (AD). Increasing evidence implicates n...The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer's disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. Using the tauopathy mouse model (P301S PS19), we demonstrate that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), inducing nuclear envelope invaginations as revealed by electron microscopy. These structural alterations are accompanied by chromatin remodeling and gene expression dysregulation. To dissect the underlying mechanism, we employed a light-inducible OptoTau system (4R1N Tau::mCherry::Cry2Olig) in human iPSC-derived neurons, enabling real-time visualization of tau aggregation dynamics. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.
Fang A, Tang X, Fleming M
… +18 more, Tancowny B, Wang X, Wang Y, Daude N, Dorosh L, Fleck SC, Rathod V, Coustou V, Cervantes SA, Velásquez CD, Westaway D, Aiken J, McKenzie D, Telling G, Stepanova M, Saupe SJ, Siemer AB, Wille H
Acta Neuropathol
· 2026 Apr · PMID 41995880
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Prion diseases are transmissible, fatal, neurodegenerative disorders driven by the conformational misfolding of the cellular prion protein (PrP) into an infectious, aggregation-prone conformer (PrP). While the accumulati...Prion diseases are transmissible, fatal, neurodegenerative disorders driven by the conformational misfolding of the cellular prion protein (PrP) into an infectious, aggregation-prone conformer (PrP). While the accumulation of PrP represents the central pathogenic event, targeting it directly and specifically has proven difficult due to its structural heterogeneity and similarity to PrP. Consequently, previous immunization efforts have largely focused on PrP, though with limited success. Here, we employed a model-based approach to design a vaccine that specifically mimics immunogenic features hypothesized to be present on the surface of PrP. By mimicking predicted surface residues and using an innocuous, cross-beta fibril scaffold derived from the fungal protein HET-s (218-289), we were able to generate unique, conformation-dependent epitopes not found on PrP. We evaluated our vaccine by immunizing a genetic prion disease mouse model of Gerstmann-Sträussler-Scheinker disease, a genetic prion disorder. Vaccination was able to significantly delay the onset of disease in immunized mice (412 ± 88 days) compared to unimmunized (177 ± 17 days) and scaffold-immunized (161 ± 27 days) animals, and supplementation with adjuvants including Freund's adjuvant (448 ± 39 days), QS-21 (479 ± 58 days), and Alum (506 ± 52 days) was able to further enhance the vaccine efficacy. To investigate the mechanism of neuroprotection, we derived a monoclonal antibody from a vaccinated mouse and mapped its discontinuous, conformation-specific epitope, comprising an aspartate-histidine pair that may be occluded in PrP, and confirmed the antibody's ability to differentiate between infectious and uninfected prion samples. Our study demonstrates the feasibility of a model-based approach for prion vaccine design and targeting of the infectious prion protein, providing groundwork for future development of not only potential prion therapeutic interventions, but also targeting related neurodegenerative disorders characterized by protein misfolding.
Zheng Y, Alzoubi I, Graeber MB
… +34 more, Anand A, Barazzuol L, Dorostkar M, Frontzek K, Golebiewska A, Hadjipanayis CG, Hortobagyi T, Ismail A, Jansen GH, Kaminska B, Kirschenbaum D, Komohara Y, Kristensen BW, Lee KS, Le Rhun E, Lu QR, Matiasek K, Mawrin C, Michelucci A, Montemurro N, Mouthon MA, Liu Q, Reimann R, Sankowski R, Schcolnik-Cabrera A, Schulz M, Schürch CM, Schwabenland M, Tchoghandjian A, Valiulytė-Simaitė I, Viapiano MS, Weiss T, Weller M, Wintermark M
Acta Neuropathol
· 2026 Apr · PMID 41991797
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This international consensus statement synthesizes key findings on the complex roles of microglia and macrophages (tumor-associated microglia/macrophages or TAMs) in glioma progression and therapeutic resistance. Recent...This international consensus statement synthesizes key findings on the complex roles of microglia and macrophages (tumor-associated microglia/macrophages or TAMs) in glioma progression and therapeutic resistance. Recent advances have highlighted the cellular, spatial, and temporal heterogeneity of TAMs, their functional plasticity, and the intricate interactions between TAMs, glioma stem cells, and the neuronal microenvironment, challenging the M1/M2 classification paradigm for TAMs in gliomas and other misconceptions. The statement emphasizes that glioma cells manipulate TAMs to suppress anti-tumor functions, while microglia-mediated modulation of neuron-glioma cell interactions promotes tumor progression. Furthermore, glioblastoma-derived extracellular vesicles (EVs) reprogram microglia to support tumor progression, offering novel therapeutic targets. To advance research and develop more effective treatments, the statement advocates for precision therapies targeting specific TAM subsets or functions, the use of bioengineered EVs as a therapeutic approach, and a shift away from simplistic terminology like "M1/M2" and "neuroinflammation". Ultimately, this new understanding can support innovative strategies to modulate the tumor microenvironment, turning immunosuppression into immunostimulation and improving outcomes for patients with glioblastoma and other types of gliomas.
Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that serves as a global epigenetic repressor. Activity-dependent Ser421-phosphorylation is permissive to translocation of mouse Mecp2 to the cytoplasm, thereby re...Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that serves as a global epigenetic repressor. Activity-dependent Ser421-phosphorylation is permissive to translocation of mouse Mecp2 to the cytoplasm, thereby reducing the repressor functions and activating neurotrophins. Mecp2-pS421 levels increase in neuron soma of AD (APP/PS1) mouse model and ablating Mecp2 increases activity of glycogen synthase kinase 3 beta, implying a link between MECP2 phosphorylation and Tau pathology in Alzheimer's disease (AD). It is currently unknown whether phosphorylation at the corresponding site of human MECP2-pS423 plays a role in AD. We developed an MECP2-pS423-specific antibody, and a quantitative selective reaction monitoring (SRM) assay based on LC-MS/MS analysis, and we used immunohistochemistry and proteomics to study MECP2-pS423 in human brain, cerebrospinal fluid (CSF), and serum specimens. In postmortem cortex and hippocampus, MECP2-pS423 expression increased across the clinicopathological spectrum of AD and correlated with histological progression and cognitive deficits. At the cellular level, MECP2-pS423 and pTau colocalized in granulovacuolar degeneration (GVD) bodies and neuritic plaques. Phosphoprotein levels of MECP2-pS423 increased in CSF and serum samples from patients clinically diagnosed as having AD premortem. Moreover, we found that a primate-specific and N-terminus truncated MECP2-E3 isoform mRNA was increased in postmortem middle temporal gyrus (MTG) of patients with AD. The results suggest that MECP2-pS423 is a promising mechanism-based biomarker and potential therapeutic target because its accumulations correlate with pathological and cognitive deficit in brain, CSF, and serum of human sporadic AD.