Autosomal-dominant frontotemporal lobar degeneration with tau pathology (FTLD-tau) is caused by pathogenic variants in the MAPT gene. Although abnormal tau aggregation is a shared endpoint, MAPT mutations produce distinc...Autosomal-dominant frontotemporal lobar degeneration with tau pathology (FTLD-tau) is caused by pathogenic variants in the MAPT gene. Although abnormal tau aggregation is a shared endpoint, MAPT mutations produce distinct cellular phenotypes and regional patterns of tau deposition, the mutation specificity and familial consistency of which remain poorly defined. We performed a systematic neuropathologic and transcriptomic analysis of brains from clinically characterized families carrying MAPT V337M, P301L, or L284L mutations. Multiple affected members per family were examined, with interfamily comparisons for P301L. Quantitative assessment of regional tau burden, cellular morphology, and co-pathologies revealed distinct, mutation-specific signatures. The V337M mutation was characterized by predominantly neuronal tau pathology with vesicular pretangles, scattered neurofibrillary tangles, and fine neurites, with minimal glial involvement. P301L exhibited prominent astrocytic tau pathology, including globular and proximal inclusions, accompanied by neuronal pretangles. L284L produced extensive oligodendroglial tau pathology with thick fibrillar coiled bodies in gray and white matter. Additional distinguishing features included hippocampal sclerosis and TDP-43 pathology in V337M; severe cortical neuronal loss and dentate fascia tau in P301L; and extensive white matter and brainstem tau, including ventral pontine neurons, in L284L. These morphologic profiles were conserved within families and, for P301L, across unrelated families. Transcriptomic analyses suggested mutation-linked expression changes concordant with cellular pathology. These findings define reproducible, mutation-specific neuropathologic and molecular signatures of MAPT-associated FTLD-tau, emphasizing the importance of genotype-driven stratification in studies of tauopathy pathogenesis.
Altendorf L, Althammer A, Roy R
… +12 more, Hack K, de Faria FW, Koch A, Thaden V, Schoof M, Schuhmann MU, Hauser P, Johann PD, Hasselblatt M, Frühwald MC, Kerl K, Schüller U
Acta Neuropathol
· 2026 Jul · PMID 42384079
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Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors during infancy and associated with a dismal prognosis. The majority of patients suffer from tumor progression or recurrence, but underl...Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors during infancy and associated with a dismal prognosis. The majority of patients suffer from tumor progression or recurrence, but underlying mechanisms remain unknown. To better understand such mechanisms, we performed single-nucleus RNA sequencing (snRNAseq) of eight paired primary tumors and recurrences. Tumor cells and cells of the tumor microenvironment (TME) were analyzed separately. Potentially therapy-resistant tumor cells were identified through the comparison of global gene expression profiles between primary and recurrent tumor cell populations using CIBERSORT. Histopathology, in vitro experiments, bulk RNA sequencing, and survival analysis were performed for validation. Paired primary and recurrent AT/RT showed significant differences in their gene expression profiles. Potentially therapy-resistant AT/RT-MYC tumor cells revealed changes in the extracellular matrix (ECM) as well as altered developmental processes and immune signaling pathways. Respective gene signatures were correlated with inferior survival in AT/RT-MYC patients. Tumor cells of relapsed AT/RT-MYC underwent partial epithelial-mesenchymal transition (pEMT), a feature that was confirmed by immunohistochemistry (IHC) and by analyzing AT/RT cells after standard therapy in vitro. Together, we identified potential mechanisms of tumor relapse and therapy resistance in AT/RT, which could be employed to improve therapy in future.
Di Bari MA, Bruno R, Riccardi G
… +13 more, Vanni I, D'Agostino C, Nonno R, De Cecco E, Burato A, Legname G, Cardone F, Moda F, Giaccone G, Catania M, Di Fede G, Tagliavini F, Agrimi U
Acta Neuropathol
· 2026 Jun · PMID 42377595
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Over the past decades, growing experimental and observational evidence has suggested that Aβ and pTau, the hallmarks of Alzheimer's disease (AD), may spread through the nervous system via a prion-like mechanism. Here, we...Over the past decades, growing experimental and observational evidence has suggested that Aβ and pTau, the hallmarks of Alzheimer's disease (AD), may spread through the nervous system via a prion-like mechanism. Here, we investigated the transmissibility of Aβ and pTau by inoculating bank voles, a wild-type rodent highly susceptible to prion diseases, with brain homogenates from four sporadic and five familial AD-affected patients. We observed that (i) neo-formed Aβ deposits and pTau inclusions were induced in recipient vole brains; (ii) Aβ pathology appeared to follow a specific neurotropic distribution; (iii) Aβ proteinopathy propagated through vole-to-vole inoculation. Our findings provide the first experimental evidence that human Aβ seeds are transmissible to a wild-type rodent model, further supporting the prion-like nature of Aβ. These results strongly support recent studies suggesting iatrogenic Aβ transmission, underscoring the need to evaluate the impact of Aβ seed exposure on human health.
Mesial temporal lobe epilepsy (mTLE) is a subtype of focal epilepsy in which approximately one-third of patients develop pharmaco-resistance, likely driven by multiple mechanisms including structural changes and dysregul...Mesial temporal lobe epilepsy (mTLE) is a subtype of focal epilepsy in which approximately one-third of patients develop pharmaco-resistance, likely driven by multiple mechanisms including structural changes and dysregulated non-coding RNAs (ncRNAs). However, our understanding of the contribution of ncRNAs to mTLE pathogenesis remains incomplete, and many classes remain uncharacterized. Notably, transfer RNAs (tRNAs) and their stress-induced fragments are emerging as important regulators of gene expression and candidate fluid-based biomarkers. However, their tissue-level expression and role in disease pathogenesis remain poorly understood. Therefore, in this study we performed profiling of tRNA and tRNA-derived fragments (tRFs), in human hippocampal and cortical samples from hippocampal sclerosis mTLE (mTLE-HS) and non-hippocampal sclerosis mTLE (mTLE non-HS) patients and postmortem controls by total RNA sequencing (RNA-seq) and small non-coding RNA sequencing (sncRNA-seq). Our data reveal widespread changes in the neural expression of pre-tRNA, tRNA and tRF expression in human mTLE brain tissue. One of the most prominent changes observed was a downregulation of 5' fragments derived from tRNA-His-GTG. Knockdown of this tRNA and its 5' fragments combined with total RNA-seq in neuronal cells identified 5'tRNA-His-GTG fragments as strong regulators of gene expression, including of epilepsy-associated genes. For example, Cannabinoid Receptor 1 (CNR1) was identified as a possible downstream target of 5'tRF-His-GTG. To investigate the contribution of 5'tRF-His-GTG to TLE pathogenesis and seizure activity, the increased expression of this tRF that was observed at 24 h after status epilepticus (SE) in mice was targeted using inhibitors. This induced increased seizures and altered network activity, with reduced theta and alpha power bands, and enhanced glial fibrillary acidic protein (GFAP) expression. Together, our study confirms and extends previous findings by identifying widespread changes in human brain tRF expression in mTLE and demonstrates for the first time that tRF manipulation affects seizure activity and mTLE pathology.
Suarez CA, Pittman SK, Inoue M
… +6 more, Lynch EM, Moran A, Merlet AN, Lacenne E, Evangelista T, Weihl CC
Acta Neuropathol
· 2026 Jun · PMID 42360470
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X-Linked myopathy with excessive autophagy (XMEA) is a rare vacuolar myopathy caused by mutations in Vma21, an assembly chaperone required for vacuolar H⁺-ATPase (V-ATPase) function. However, the mechanisms linking Vma21...X-Linked myopathy with excessive autophagy (XMEA) is a rare vacuolar myopathy caused by mutations in Vma21, an assembly chaperone required for vacuolar H⁺-ATPase (V-ATPase) function. However, the mechanisms linking Vma21 deficiency to progressive muscle pathology remain poorly understood, in part due to the lack of suitable animal models. To address this gap, we generated conditional Vma21 knockout mouse models to investigate the consequences of Vma21 loss in striated muscle. Combined deletion of Vma21 in skeletal and cardiac muscle resulted in early lethality driven by severe cardiomyopathy associated with autophagic dysregulation, preceding the development of skeletal muscle pathology. In contrast, inducible skeletal muscle-specific deletion of Vma21 produced progressive muscle weakness and myopathy characterized by centralized nuclei, fiber splitting, and increased fiber size variability. Affected skeletal muscle also recapitulated defining pathological hallmarks of XMEA, including basal lamina reduplication and autophagic vacuoles with sarcolemmal features (AVSFs). Ultrastructural analysis revealed membrane-bound vacuoles containing partially undegraded material that frequently accumulated at the subsarcolemmal region, together with clusters of vesicular structures. Notably, mutant muscle exhibited increased staining for the late endosomal/exosomal marker CD63, which strongly colocalized with the complement membrane attack complex C5b-9. A similar increase in CD63 staining and its colocalization with C5b-9 were observed in skeletal muscle biopsies from patients with XMEA. Together, these models faithfully recapitulate key pathological features of XMEA and identify the accumulation of CD63-positive structures and their colocalization with C5b-9 as previously unrecognized features of Vma21-deficient skeletal muscle, implicating altered vesicle trafficking in XMEA pathogenesis.
Lütje L, Chen JQA, Hamann J
… +3 more, Smolders J, Huitinga I, van den Bosch AMR
Acta Neuropathol
· 2026 Jun · PMID 42350827
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Multiple sclerosis (MS) shows pronounced pathological and clinical variability between individuals, reflecting differences in genetic susceptibility, inflammatory activity, and tissue repair. This variability complicates...Multiple sclerosis (MS) shows pronounced pathological and clinical variability between individuals, reflecting differences in genetic susceptibility, inflammatory activity, and tissue repair. This variability complicates efforts to relate lesion pathology to clinical trajectories. In previous work in the Netherlands Brain Bank MS autopsy cohort (NBB-MS), we showed that relative proportions of different lesion types, lesion load, and microglia/macrophage activity score, associate with clinical severity, while also revealing marked inter-individual variability. Here, we extend these observations by examining whether selected donor-specific pathological features relate to genetic background, quantitative lesion type distributions, and clinical disease course, and thereby help contextualize this heterogeneity.Brain tissue from 287 NBB-MS donors was assessed for the presence of the donor-specific pathological features, namely perivascular cuffs, microglial nodules, broad rim lesions (BRLs), and remyelination efficiency. Perivascular cuffs and microglial nodules were more prevalent among carriers of the MS susceptibility allele HLA-DRB1*15:01 (rs3135388). BRLs and perivascular cuffs were enriched in carriers of the MS severity-associated SNP in the DYSF-ZNF638 locus (rs10191329). Perivascular cuffs associated with increased microglia/macrophage activation score and decreased age at death. Microglial nodules in the normal appearing white matter associated with a higher proportion of active lesions. BRLs were linked to increased proportions of active and mixed active/inactive lesions, higher brainstem lesion rate, and a higher age related MS severity score. Poor remyelination efficiency associated with a higher proportion of mixed active/inactive and inactive lesions, and a shorter disease duration.Together, these findings show that specific pathological features of donors relate to genetic risk, lesion type distribution, and clinical outcome. Integrating these donor-specific pathological features alongside lesion classification will enable a more biologically refined interpretation of post-mortem MS tissue study results and will improve understanding of inter-individual heterogeneity in MS.
Kac PR, Cousins KAQ, Szadziewska A
… +13 more, Shaw LM, Turton M, Van Deerlin VM, Harrison P, Zetterberg H, Wolk DA, McMillan CT, Galasko D, Hanrieder J, Lee EB, Kvartsberg H, Irwin DJ, Blennow K
Acta Neuropathol
· 2026 Jun · PMID 42340485
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Across tauopathies-Alzheimer's disease (AD), frontotemporal lobar degeneration due to tau (FTLD-tau)-we compared cerebrospinal fluid (CSF) biomarkers of phosphorylated-tau (p-tau) p-tau181, p-tau212, tau368, total tau (t...Across tauopathies-Alzheimer's disease (AD), frontotemporal lobar degeneration due to tau (FTLD-tau)-we compared cerebrospinal fluid (CSF) biomarkers of phosphorylated-tau (p-tau) p-tau181, p-tau212, tau368, total tau (t-tau), and the tau368/t-tau ratio, and tested differentiation from non-tau (FTLD-TDP, neuronal α-synuclein disease (αSyn), and controls). In AD, CSF p-tau181 and p-tau212 were significantly higher than in all other groups, including FTLD-tau, while tau368/t-tau was significantly lower. With the aim to combine tau phosphorylation biomarkers (p-tau181 and p-tau212) with biomarkers for severity of tau pathology (tau368), we made ratios between these biomarkers and examined their diagnostic accuracy in FTLD after excluding high/intermediate AD neuropathologic change (ADNC). CSF p-tau181 and p-tau212, as well as p-tau181/tau368 and p-tau212/tau368, were higher in FTLD-tau compared with non-tau groups, and the diagnostic accuracy to discriminate FTLD-tau from FTLD-TDP improved. Levels of the ratios were increased in behavioral and primary progressive aphasia variants of tauopathies when compared to FTLD-TDP. Furthermore, the biomarkers showed significant correlation with both FTLD-tau and AD tau burden at autopsy across brain regions. These results suggest unique patterns of increased relative levels of p-tau epitopes in CSF among ADNC and FTLD-tau could improve the diagnosis of tauopathies and inform inclusion criteria in clinical trial design.
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease found in individuals with a history of repetitive head injury (RHI) received through playing contact sports. Currently, CTE can only be di...Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease found in individuals with a history of repetitive head injury (RHI) received through playing contact sports. Currently, CTE can only be diagnosed after death through the identification of perivascular neuronal hyperphosphorylated tau (pTau) pathology, found at the depth of the cortical sulcus. Although the pathognomonic lesion is found among all cases, pTau deposition is patchy and heterogeneous among individuals. To determine whether the heterogeneity of CTE masks more subtle ordering or additional disease variants, we applied the unsupervised machine learning algorithm subtype and stage inference (SuStaIn) on fully quantitative pTau density data from 26 brain regions in 207 CTE cases and 75 control cases. SuStaIn identified three distinct pathological progression subtypes: 93 cases were classified as Subtype 1 (cortical predominant) and showed dense, rapidly progressing cortical pTau akin to the classically described CTE neuropathology; Subtype 2 (cortical sparing-hippocampal enhanced) had 105 cases that exhibited a reduced cortical pTau burden that progressed slower, but also had pronounced hippocampal involvement in a CTE-specific pattern; and Subtype 3 (copathology altered) consisted of 28 older cases with higher CTE stage, was enriched for comorbid pathologies (pTDP43, Aβ, hippocampal sclerosis, and arteriolosclerosis), and had enhanced pTau in regions highly related to those additional pathologies. Clinically, impaired performance in the Functional Activities Questionnaire (FAQ) correlated with pTau regional burden and severity only in cases with Subtype 1 pathology, suggesting the enhanced cortical pTau pathology was linked to greater functional decline. Overall, these findings help characterize the heterogeneity in CTE progression, validate key pathological variants, and will be crucial for refining diagnostic criteria and advancing in-life diagnosis.
Acta Neuropathol
· 2026 Jun · PMID 42301522
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Fluid and imaging biomarker data show that anti-amyloid (Aβ) antibodies promote the clearance of Aβ from the brains of patients with Alzheimer's disease (AD). We examined postmortem brain tissue of individuals who partic...Fluid and imaging biomarker data show that anti-amyloid (Aβ) antibodies promote the clearance of Aβ from the brains of patients with Alzheimer's disease (AD). We examined postmortem brain tissue of individuals who participated in aducanumab clinical trials and investigated the drug's effects on Aβ pathology and other AD phenotypes. The medial temporal lobe of six aducanumab clinical trial participants-who had extensive exposure to aducanumab and happened to die between 7 weeks and 5 years after their last antibody infusion-was compared with that of nine untreated AD patients matched for age, APOE genotype, and Braak neurofibrillary tangle stage, to determine how aducanumab impacts AD pathobiology. Patients treated with aducanumab displayed a robust reduction in Aβ burden. As observed in previous studies, Aβ was associated with non-arterial microvessels in aducanumab-treated patients, suggesting a redistribution of Aβ within the neuropil. Neuritic phospho-tau decreased in parallel with fewer Aβ plaques, but the density of PHF-1 and AT8 neurofibrillary tangles remained unchanged relative to the average untreated AD donor. Measures of microglial and astroglial reactivity were also comparable to those in untreated AD controls. These findings confirm aducanumab's potent ability to target and remove brain Aβ. On average, Aβ plaques increased in proportion to the length of time after the last dose, consistent with the idea that plaques gradually redeposit post-treatment. The selective reduction of neuritic, but not neurofibrillary tangle phospho-tau implies that Aβ-targeted antibodies such as aducanumab alleviate plaque-associated dystrophy but may not address established tangles. This study describes the long-term outcomes of anti-Aβ immunotherapy in AD.
Fancy NN, Willumsen N, Chau VMN
… +21 more, Boulger SL, Whitwell HJ, Wang W, Avot B, Thomas M, Talbot-Martin J, Tsartsalis S, Khozoie C, McGarry A, Schneegans E, Yagoubi R, Cheung TKD, Papageorgopoulou M, Adair E, Cooper B, Davey K, Smith AM, Scotton W, Hardy J, Matthews PM, Jackson JS
Acta Neuropathol
· 2026 Jun · PMID 42298074
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TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer's disease (AD). Genetic polymorphisms reducing expression of the functionally related protein CD33 are prot...TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer's disease (AD). Genetic polymorphisms reducing expression of the functionally related protein CD33 are protective. Here we have contrasted cellular pathology in human post-mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by R47H and R62H TREM2 variants (TREM2var) with and without heterozygosity for the protective rs3865444 CD33 polymorphism. Epistasis between CD33 and TREM2 was demonstrated by relative normalisation of differences in β-amyloid load in TREM2var carriers of the protective CD33 allele. These functional differences were mirrored by differential microglial transcriptomic responses to β-amyloid. Controlling for CD33 genotype, microglial transcriptional responses to increasing β-amyloid were lower for TREM2var, particularly for R47H compared to CV, and there was a reduction in expression of neuroplasticity pathways in TREM2var. R62H microglial signatures were distinguished from those of R47H by upregulation of genes associated with phagocytosis and from CV by differences in inflammatory gene expression including those involved in NF-kappaB signalling. Differential gene expression with increasing β-amyloid also suggested upregulation of β-amyloid production and binding pathways in excitatory neurons in TREM2var heterozygotes. There was lower enrichment for pathways positively adaptive to pathology and expressed in inhibitory neurons from CV samples for both TREM2var. Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue not found for the TREM2var, which showed evidence of increased β-amyloid formation and neuroplasticity changes. Together, these results highlight differences in molecular pathology between CV and TREM2var and between the TREM2var risk variants. They highlight mechanisms of AD risk mediated by secondary effects on astroglial and neuronal functions. Demonstration of strong epistasis between TREM2 and CD33 with AD supports the therapeutic potential of modulators of CD33 inhibition or expression.
Seiffer S, Rotter J, Brendler J
… +7 more, Ricken A, Detzer Z, Braune M, Schöneberg T, Schulz A, Winter K, Bechmann I
Acta Neuropathol
· 2026 Jun · PMID 42295430
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Microglia are the resident immune cells of the human central nervous system and play key roles in development, homeostasis, and disease. These functions are mediated by a broad repertoire of cell-surface receptors, inclu...Microglia are the resident immune cells of the human central nervous system and play key roles in development, homeostasis, and disease. These functions are mediated by a broad repertoire of cell-surface receptors, including G protein-coupled receptors such as the ADP receptor P2Y12 and GPR34, a receptor for lysophosphatidylserine. While GPR34 deficiency has been linked to impaired microglial phagocytosis, its regulation in relation to amyloid-β (Aβ) and tau pathology in Alzheimer's disease (AD) remains unclear. We performed a quantitative analysis of microglial density, morphology, and GPR34 expression in the medial temporal lobe cortex (MTLC) of elderly human body and tissue donors across the AD spectrum. Using fluorescence in situ hybridization and immunolabeling, we analyzed 187,670 microglial cells and correlated microglial parameters with the severity and spatial proximity of Aβ plaques and tau inclusions. In parallel, we analyzed human single-nucleus RNA sequencing data from 236,002 cells to assess GPR34 expression across microglial subtypes, brain regions, and neuropathological stages. Microglial density and overall morphology in the MTLC were largely preserved, independent of local Aβ or hyperphosphorylated tau burdens. Apart from a moderate shortening of microglial processes in the immediate vicinity of Aβ plaques, no consistent pathology-associated morphological changes were detected. GPR34 expression showed pronounced cell-to-cell variability and differed across microglial subtypes and brain regions, but neither expression intensity nor the proportion of GPR34-positive microglia correlated consistently with Braak stage or Thal phase. These findings suggest that GPR34 regulation in human microglia is highly context-dependent and shaped by regional and cellular heterogeneity rather than AD-associated pathology alone.
Dunot J, Gandin C, Truchi M
… +14 more, Pirro G, Moreno S, Launay A, Azoulay B, Landra H, Yishan SM, Buée L, Lebrigand K, Pousinha PA, Blum D, Mari B, Bethus I, Willem M, Marie H
Acta Neuropathol
· 2026 Jun · PMID 42237024
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Alzheimer's disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-β and Tau remain central to AD pathogenesis, molecular triggers...Alzheimer's disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-β and Tau remain central to AD pathogenesis, molecular triggers of synapse weakening remain unclear. Here, we investigated AETA, a novel brain-secreted peptide derived from amyloid precursor protein (APP), as a potential mediator of synapse dysfunction in AD. We previously identified AETA as a unique modulator of NMDA receptor activity in the healthy brain; however, its role in AD etiology was yet to be explored. Post-mortem analyses of human hippocampal and prefrontal cortex tissues revealed significantly elevated AETA levels in AD patients, particularly in females. To further explore the contribution of AETA to AD synaptic pathology, we analyzed a new mouse model, the AETA-m mouse, exhibiting chronically increased brain AETA expression. Hippocampi of female AETA-m mice displayed an increase in the number of astrocyte and microglia, but no overt neuroinflammation. RNA sequencing of female AETA-m hippocampi revealed alterations in synaptic gene expression that closely paralleled those observed in vulnerable human AD brain regions, most notably in the hippocampus. These two phenotypes were absent in males. Functionally, hippocampal neurons from AETA-m mice displayed impaired NMDA receptor signaling, dendritic spine loss, and memory deficits especially in females, mirroring early AD-associated synaptic dysfunction. Together, these findings identify AETA as a novel key contributor of synaptic vulnerability in AD and associated memory processing, especially in females. Targeting AETA signaling may therefore offer new therapeutic avenues for preventing or mitigating synaptic and cognitive decline in AD.
Leboeuf M, Nijssen J, Comley LH
… +10 more, Aguila Benitez JC, Mei I, Gómez Alcalde S, Muñoz de Bustillo-Alfaro RA, Radoi V, Nichterwitz S, Schweingruber C, Acevedo Arozena A, Hedlund E, Cullheim S
Acta Neuropathol
· 2026 May · PMID 42213237
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Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons (MNs). Why these neurons are particularly vulnerable in ALS remains unclear, as does why certain MN groups remain resistant thro...Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons (MNs). Why these neurons are particularly vulnerable in ALS remains unclear, as does why certain MN groups remain resistant throughout the disease course. We investigated the role of the human leukocyte antigens (HLAs) and beta2-microglobulin (β2m) in MN susceptibility to ALS, given their reported involvement in both prolonging and shortening disease progression. Loss of HLAs in ALS has also been shown to increase MNs vulnerability to toxicity exerted by activated astrocytes. RNA sequencing of control tissues demonstrated that disease-resistant oculomotor neurons (OMNs) and Onuf's MNs exhibited β2m and HLA mRNA levels comparable to those of vulnerable spinal MNs, suggesting that baseline differences in these transcripts do not explain the differential vulnerabilities of these MN groups. However, HLA protein levels showed an inverse correlation with spinal MN size, with the large MNs, those lost early in ALS, displaying the lowest HLA expression. HLA protein levels were also reduced in spinal MNs from end-stage ALS patient tissues, while remaining relatively unchanged in OMNs. In contrast, spinal MNs uniquely exhibited significant upregulation of β2m and HLA-C transcripts during disease, likely reflecting a protective compensatory response. Together, these findings suggest that β2m and HLAs may contribute to spinal MN vulnerability in ALS. To assess their functional role, β2m knockout mice were crossbred with SOD1G93A ALS mice. Loss of β2m did not alter life span of the ALS mice, but led to partial preservation of lumbrical muscle innervation that was insufficient to maintain motor function. Analysis of GFAP immunoreactivity revealed marked neuroinflammation activation in the spinal cords of β2m knockout mice. As these mice retain normal MN numbers and life-span, this indicates that loss of functional MHC-I, even in the presence of astrocyte activation, is insufficient to cause MN disease. Furthermore, β2m knockout significantly increased GFAP activation in SOD1G93A mice, but did not further exacerbate disease progression, suggesting that loss of functional MHC-I does not necessarily render MNs more vulnerable to astrocyte toxicity. Overall, these findings indicate that β2m and HLAs are dynamically regulated in ALS, and may influence MN vulnerability, but they are not major disease modifiers in ALS.
Tsuchiya T, Miyawaki S, Hirano Y
… +18 more, Sakai Y, Ohara K, Inoue Y, Komura D, Shinozaki-Ushiku A, Ogawa S, Sato D, Hongo H, Hirata S, Teranishi Y, Ono H, Otani Y, Takami H, Ushiku T, Ishikawa S, Tanaka S, Ichimura K, Saito N
Richardson TE, Cherry J, Kandoi S
… +39 more, Rohde SK, Uretsky M, Tuz-Zahra F, Bieniek KF, Farrell K, Hefti MM, Miller MB, Tripodis Y, Stein TD, Maldonado-Díaz C, Hiya S, Beach TG, Corrada MM, Dugger BN, Flanagan ME, Frosch MP, Gearing M, Grinberg LT, Hansen LA, Hawes D, Head E, Keene CD, Kofler J, Lee EB, Nelson PT, Oakley DH, Perrin RJ, Rissman RA, Salamat S, Schneider JA, Serrano GE, Teich AF, Troncoso JC, Wisniewski T, Woltjer RL, Crary JF, Dickson DW, McKee AC, Walker JM
Acta Neuropathol
· 2026 May · PMID 42184025
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Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with th...Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with the topographical distribution of β-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs). While cognitive decline correlates with the level of ADNC, there remains a great deal of variation in cognitive outcomes between individuals that is unaccounted for by current neuropathologic evaluation metrics. We leveraged quantitative computer-assisted positive pixel assessments to establish the neocortical p-tau burden in the middle frontal and superior temporal gyri of 61 individuals with Braak NFT stage V who had a wide range of cognitive outcomes and trajectories. Frontal and temporal neocortical p-tau burden varied between 0.2% and 53.7%. Both frontal and temporal p-tau burden directly affected cognitive outcome and correlated with function of multiple cognitive domains, including measures of language/semantic memory and attention/working memory. In multivariable analysis, only p-tau burden and microinfarcts significantly impacted cognitive decline, while Aβ, limbic-predominant age-related TDP-43 encephalopathy, Lewy body pathology, and other measures of cerebrovascular disease did not. Additionally, individuals with low mean neocortical p-tau burden (≤ 13%) had significantly better longitudinal cognitive trajectories over the final 15 years of life compared to those with high burden (≥ 23.5%). These results suggest that while all individuals with Braak stage V have some degree of neurofibrillary degeneration in the neocortex, the significant variation in cognitive decline observed between these individuals can be partially understood as a reflection of the variation in quantitatively assessed neocortical p-tau burden, which had a greater impact on progression to dementia than common comorbid neuropathologies associated with dementia risk. This argues for the incorporation of the density of ADNC-related pathology, in addition to its regional location, as an adjunct to future staging systems for Alzheimer disease.
Singh A, Denkinger MN, Leuzy A
… +22 more, Dieckhoff K, Liu J, Marques TM, Monuki E, Stark C, Grill JD, Hom C, Sultzer D, Doran E, Lott I, Wood K, Gawronski B, Gonzalez L, Choudhury P, Atri A, Beach TG, Serrano GE, Sajjadi SA, Van Keuren-Jensen K, Reiman EM, Head E, Ashton NJ
Acta Neuropathol
· 2026 May · PMID 42162487
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Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages...Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90% of individuals with Alzheimer's disease (AD) exhibit some level of CAA. Notably, in the new era of disease-modifying treatments for AD, CAA is a significant risk factor for amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-amyloid treatments. Therefore, there is great need for accessible, reliable and accurate in vivo biomarkers (e.g., blood-based) to improve antemortem identification of CAA that would improve risk stratification and reduce symptomatic ARIA. In this study, we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for exploratory biomarker quantification in antemortem plasma of participants with neuropathological assessments for CAA from the Banner Sun Health Research Institute Brain and Body Donation Program (N = 251) and independently validated in the University of California Irvine Alzheimer Disease Research Center cohort (N = 110). We evaluated the differential protein expression in antemortem plasma sample taken < 5 years (mean 1.76 ± 1.3) from death using a logistic regression model. We further compared multi-biomarker models and found that a combination of CRP, IL4, CCL11, NPY and PDLIM5, plus demographic covariates showed an area under the curve (AUC) of 0.90 (95% CI 0.86-0.94) to identify neuropathologically confirmed CAA in the discovery cohort. In our independent replication, the antemortem plasma signature performed better than the basic demographics model showing a potential to predict CAA. The exploration and validation in antemortem plasma indicate that a multi-analyte panel, when combined with in vivo blood biomarkers for AD pathology, may be capable of identifying the presence of CAA and could have an meaningful impact on the clinical evaluation of patients under the investigation for cognitive decline. Further developments in biomarkers for this condition are crucial so that CAA identification could inform treatment decisions by highlighting ARIA risk.
Girodengo M, Mihaylov SR, Klonowska K
… +9 more, Mantoan Ritter L, Flynn HR, Skehel JM, Bou Farhat E, Aronica E, White M, Kwiatkowski DJ, Ultanir SK, Bateman JM
Acta Neuropathol
· 2026 May · PMID 42162382
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Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in TSC1 and TSC2, resulting in activation of mechanistic target of rapamycin complex 1 (mTORC1). Neurological manifestations in TSC patients include...Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in TSC1 and TSC2, resulting in activation of mechanistic target of rapamycin complex 1 (mTORC1). Neurological manifestations in TSC patients include epilepsy, autism and intellectual disability. Two types of brain lesions, cortical tubers and subependymal giant cell astrocytomas (SEGAs), cause the majority of neurological manifestations in TSC. We have limited understanding of the molecular changes that occur in tubers and SEGAs and how these contribute to disease pathogenesis. To investigate this, we performed proteomic and phosphoproteomic analysis of TSC patient tuber and SEGA tissue. Tubers showed evidence of alterations in mitochondrial respiration, cytoskeleton organisation and neuronal function. However, we were unable to detect mTORC1 activation in tubers, likely due to the small number of cells with complete inactivation of TSC1 or TSC2. By contrast, SEGAs showed evidence of strong mTORC1 activation and large-scale changes in the proteome and phosphoproteome. SEGAs exhibited increased expression of ribosomal proteins and activation of a neuroinflammatory response. Phosphoproteomics identified 6060 phosphosites within 2154 proteins increased in SEGAs. Phosphorylation of multiple proteins involved in RNA-metabolism, including mRNA splicing, was increased in SEGAs. Consistent with this, we found evidence of extensive alterations in mRNA transcript splicing in SEGA tissue that is shared with a wide range of cancers. These data greatly expand the repertoire of known mTORC1 target proteins in the human brain and reveal that large-scale mis-regulation of mRNA splicing may promote the formation of SEGAs in TSC.
Govaerts CW, van Dijk JMC, van der Hoorn A
… +1 more, Kruyt FAE
Acta Neuropathol
· 2026 May · PMID 42154325
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Recent clinical trials have demonstrated the efficacy of different modalities of systemic therapy in treating brain metastases, including immune checkpoint inhibitors and various types of targeted therapy. These findings...Recent clinical trials have demonstrated the efficacy of different modalities of systemic therapy in treating brain metastases, including immune checkpoint inhibitors and various types of targeted therapy. These findings expand treatment options for these intracranial tumours, which are linked to significant morbidity and poor outcomes. Despite these advances, important challenges remain. These include the difficulty of identifying predictors of intracranial response to such therapies. The intracranial activity of anti-tumour agents is dependent on the complex interplay between the cellular components of the tumour microenvironment, consisting of both brain-resident cell types and peripheral immune cells. A deeper understanding of these interactions is essential for identifying mechanisms that contribute to inter- and intratumoural heterogeneity in treatment sensitivity. This review provides a comprehensive overview of the mechanisms by which the constituent cell types of the tumour microenvironment of brain metastases contribute to tumour progression and therapy resistance. Herein, a conceptual model of the relevant biological pathways is outlined along with references to how specific vulnerabilities could be utilised to develop more effective therapeutic strategies.