Yamashita T, Yokota O, Ousaka D
… +14 more, Sun H, Haraguchi T, Ota-Elliott RS, Matsuoka C, Kawano T, Nakashima-Yasuda H, Fukui Y, Nakano Y, Morihara R, Hasegawa M, Hosono Y, Terada S, Takaki M, Ishiura H
Acta Neuropathol
· 2025 Aug · PMID 40802071
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms...Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in DNAJC7, a member of the HSP40 family. All three patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Pathological examination revealed degeneration of both upper and lower motor neurons, with phosphorylated TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortices. Immunoblot analysis were consistent with a type B pattern of phosphorylated TDP-43 in the precentral gyrus. Immunohistochemistry and RNA sequencing analyses demonstrated a substantial reduction in DNAJC7 expression at both the protein and RNA levels in affected brain regions. In a TDP-43 cell model, DNAJC7 knockdown impaired the disassembly of TDP-43 following arsenite-induced stress, whereas DNAJC7 overexpression suppressed the assembly and promoted the disassembly of arsenite-induced TDP-43 condensates. Furthermore, in a zebrafish ALS model, dnajc7 knockdown resulted in increased TDP-43 aggregation in motor neurons and reduced survival. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in DNAJC7 to familial ALS with TDP-43 pathology.
Mikkelsen MK, Li X, Yu K
… +30 more, High AA, Tan H, Furtado LV, Leelatian N, Bell J, Berry JD, Boué DR, Chien F, Coven SL, Dewan MC, Fangusaro J, Foster JB, Hoffman L, Kofler JK, Larkin T, Lazow M, May A, Mobley BC, Noun D, Posorske B, Schwartz J, Sheila I, Spiller S, Tanaka R, Qaddoumi I, Tinkle CL, Peng J, Robinson GW, Moreira DC, Chiang J
Acta Neuropathol
· 2025 Aug · PMID 40788548
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Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare, and optimal treatment remains undefined. We aim to comprehensively characterize their clinical and molecular features, offering granular insights into present...Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare, and optimal treatment remains undefined. We aim to comprehensively characterize their clinical and molecular features, offering granular insights into presentations and therapies to elucidate prognostic factors and therapeutic targets. Histologic, molecular, and clinical data of 30 patients with DLGNT were analyzed. Median age at diagnosis was 7.5 years (range: 0.9-20 years). Disease was localized at diagnosis in 16 patients (53.3%), predominantly in the spinal cord (14/16, 87.5%). KIAA1549::BRAF fusion occurred in 27 (96.4%) of 28 patients. DNA methylation profiling of 23 tumors classified 4 (17.4%) as DLGNT MC-1, 3 (13.0%) as DLGNT MC-2, and 16 (69.6%) as DLGNT, but not to a specific subclass. Median follow-up was 57.5 months. Most patients (90.0%) received adjuvant therapy. Chemotherapy was the first-line adjuvant therapy in 19 patients (70.4%); targeted therapy in 5 patients (18.5%), and radiotherapy in 2 patients (7.4%). Median progression-free survival (PFS) after first chemotherapy, targeted therapy, or radiotherapy was 44 (1-77) months, 18 (4-39) months, and 16.5 (9-23) months, respectively. Five-year PFS was 15.9% ± 8.0, and 5 year overall survival (OS) was 83.3% ± 8.8. Patients older than 9 years at diagnosis (p = 0.002) and those with MC-2 (p = 0.04) had worse 5 year OS. Multi-omic analysis revealed simultaneous activation of multiple signaling pathways, which may serve as potential therapeutic targets. DLGNT remains challenging to treat, with poor outcomes across modalities. Further investigation of treatment, including targeted therapies addressing activated pathways, is needed to improve patient survival.
Alidadiani S, Faura J, Wynants S
… +42 more, Peeters N, Van den Broeck M, De Witte L, Policarpo R, Cheung S, Pottier C, Ghayal NB, Mol MO, van Blitterswijk M, Udine E, DeJesus-Hernandez M, Baker M, Finch NA, Asmann YW, van Rooij JGJ, Nguyen AT, Ross Reichard R, Nana AL, Lopez OL, Boxer AL, Rosen HJ, Spina S, Herms J, Josephs KA, Petersen RC, Rissman RA, Hiniker A, Ang LC, Grinberg LT, Halliday GM, Boeve BF, Graff-Radford NR, Seelaar H, Neumann M, Kofler J, White CL, Seeley WW, van Swieten JC, Dickson DW, Mackenzie IRA, De Coster W, Rademakers R
Acta Neuropathol
· 2025 Aug · PMID 40783910
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Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of pr...Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Cell-type deconvolution revealed loss of excitatory neurons and a higher proportion of astrocytes in aFTLD-U relative to controls. Differential gene expression and co-expression network analysis, adjusted for the shift in cell-type proportions, showed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of the Sonic hedgehog (Shh) pathway, including the GLI1 transcription factor, in aFTLD-U. Overall, oligodendrocyte and astrocyte-enriched genes were significantly over-represented among the differentially expressed genes. Differential splicing analysis confirmed the dysregulation of non-neuronal cell types with significant splicing alterations, particularly in oligodendrocyte-enriched genes, including myelin basic protein (MBP), a crucial component of myelin. Immunohistochemistry in frontal cortex brain tissue also showed reduced myelin levels in aFTLD-U patients compared to controls. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET.
Muñoz González G, T Hart BA, Bugiani M
… +4 more, Plemel JR, Schenk GJ, Kooij G, Luchicchi A
Acta Neuropathol
· 2025 Aug · PMID 40783892
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Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease, traditionally characterized by the presence of focal demyelinating lesions in the CNS. However, accumulating evidence suggests that multip...Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease, traditionally characterized by the presence of focal demyelinating lesions in the CNS. However, accumulating evidence suggests that multiple sclerosis pathophysiology extends beyond such classical lesions, affecting also 'normal' appearing tissue in both white and gray matter, referred to as 'normal-appearing white matter' and 'normal-appearing gray matter', respectively. Here, we provide a comprehensive overview of the widespread biochemical, cellular, and microstructural alterations occurring in these 'normal-appearing' CNS regions. Additionally, we discuss the evidence derived from human post-mortem studies that support that normal-appearing white and gray matter could be the drivers of smoldering-associated pathological worsening once repair mechanisms are exhausted. Comprehensive understanding of multiple sclerosis pathology beyond classical lesions not only provides a more complete picture of disease progression, but also provides further insights into potential novel therapeutic avenues in order to slow or halt disability accumulation.
Kim JW, Nam SH, Lee GS
… +6 more, Chung HY, Kim EY, Han JP, Jang JH, Choi BO, Yeom SC
Acta Neuropathol
· 2025 Aug · PMID 40760337
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Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (MORC2), which leads to elevated hydroxyl radical levels, reduced A...Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (MORC2), which leads to elevated hydroxyl radical levels, reduced ATPase activity, and apoptosis-mediated neuromuscular degeneration. CMT2Z presents with severe clinical manifestations, yet no widely applicable and affordable treatment has been developed. While gene therapy presents a theoretical solution, its feasibility remains constrained by prohibitive costs and delivery challenges. We observed sex-specific differences in muscle function in a CMT2Z mouse model carrying the microrchidia CW-type zinc finger protein 2A (Morc2a) p.S87L variant, with males exhibiting more severe weakness, suggesting a protective role of estradiol in females. Thus, we hypothesized that identifying and utilizing this factor could contribute to CMT2Z drug development. We found that estradiol stabilizes the Morc2a variant protein by inhibiting autophagy, independently of specific estrogen receptors, thereby mitigating hydroxyl radical-induced mitochondrial aggregation and apoptosis while restoring ATPase function. Subcutaneous implantation of estradiol pellets in the CMT2Z mouse model significantly improved Morc2a protein stability in the quadriceps femoris and sciatic nerve, reversed mitochondrial aggregation, and ameliorated both muscular and peripheral nerve degeneration. Notably, symptomatic Morc2a p.S87L mice exhibited robust peripheral nerve regeneration, demonstrating estradiol's ability to restore function rather than merely delay disease progression. Moreover, the therapeutic effects were reproduced in human MORC2 p.R252W variants, further confirming its translational potential. As an FDA-approved compound with well-characterized pharmacokinetics, estradiol represents a rapidly deployable strategy for treating CMT2Z. This study highlights the pivotal role of oxidative stress in the pathophysiology of CMT2Z and identifies MORC2 stabilization as a promising intervention. Moreover, the findings advocate for repurposing existing therapeutics to address rare genetic disorders, broadening treatment paradigms for neuromuscular diseases beyond CMT2Z.
Keck MK, Al-Hussaini M, Amayiri N
… +33 more, Yiadom AAB, Chamyan G, Cheesman E, Faure-Conter C, Garcia-Ariza M, Gauchotte G, Hasselblatt M, Jorgensen M, Kilday JP, Lamas G, Lavarino C, Li MM, Lubieniecki F, Maher OM, Meyronet D, Mueller J, Santi M, Schüller U, Seidinger AL, Sill M, Sudhakar S, García MT, Tauziede-Espariat A, Varlet P, Vasiljevic A, Wittmann A, von Deimling A, Solomon DA, Sahm F, Tietze A, von Hoff K, Sievers P, Jones DTW
Acta Neuropathol
· 2025 Aug · PMID 40751809
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CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS t...CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the PLAGL1- and PLAGL2-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative PLAG1 fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5' fusion partners (ASAP1, ADGRG1, TMEM68, TCF4, CHD7, NCALD, HNRNPK, LOC105378102) were identified that upregulate wild-type PLAG1 through promoter hijacking. Expression analysis shows upregulation of PLAG1 as well as IGF2, DLK1, Desmin, CYP2W1, and RET, which are also robustly expressed in PLAGL1/2-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to PLAGL1/2-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.
Kivistö V, Englert B, Tuimala J
… +18 more, Kok E, Puttonen H, Raunio A, Karhunen PJ, Lehtinen MK, Borghammer P, Ahvenainen E, Colangelo K, Savola S, Tanskanen M, Kaivola K, Tienari PJ, Kumar D, Paetau A, Tynninen O, Mäyränpää MI, Polvikoski T, Myllykangas L
Acta Neuropathol
· 2025 Aug · PMID 40748411
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Cardiac manifestations are associated with Lewy body disease, but studies addressing the underlying histopathological mechanisms at the myocardial level are sparse. Here, we generated an artificial intelligence-based alg...Cardiac manifestations are associated with Lewy body disease, but studies addressing the underlying histopathological mechanisms at the myocardial level are sparse. Here, we generated an artificial intelligence-based algorithm to quantify tyrosine hydroxylase (TH)-immunoreactive sympathetic distal axons at the myocardial level. This novel tool was applied to septal samples of the Vantaa 85 + study (n = 138), which is a population-based autopsy study representing all subjects aged 85 years or older living in the city of Vantaa (southern Finland) in 1991. In addition, the tool was applied to left ventricle samples of the Helsinki Biobank (n = 87) and the forensic Tampere Sudden Death Study (TSDS, n = 127). The level of myocardial TH reactivity was compared between subjects with and without Lewy pathology in the central nervous system in all datasets. In the Vantaa 85 + study, TH reactivity was also compared between subjects with caudo-rostral and amygdala-based subtypes, and potential confounding factors (age at death, sex, myocardial infarction, senile systemic amyloidosis, and diabetes medication) were controlled for using multiple linear regression models. Presence of Lewy pathology was strongly associated with loss of TH reactivity at the myocardial level in all three autopsy cohorts (Vantaa 85 + p = 0.001, Helsinki Biobank p < 0.001, TSDS p < 0.001)). In the Vantaa 85 + study, the caudo-rostral subtype (p < 0.001), but not the amygdala-based subtype (p = 0.60), was associated with myocardial denervation/dysfunction, and this association was independent of other known causes of sympathetic denervation/dysfunction. Caudo-rostral subtype and myocardial infarction were the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population (Vantaa 85 +). In conclusion, our results show that Lewy pathology in the central nervous system, and particularly its caudo-rostral subtype, is strongly associated with loss of sympathetic distal axons at the myocardial level. We also provide evidence that the caudo-rostral subtype is one of the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population.
Tuddenham JF, Fujita M, Lee E
… +21 more, Nimmagadda N, Khairallah A, Harbison C, Flowers XE, Coronas-Samano G, Maniatis S, Daly A, Schneider JA, Teich AF, Vonsattel JPG, Sims PA, Elyaman W, Bradshaw EM, Ostrow LW, Phatnani H, Shneider NA, Bennett DA, De Jager PL, Przedborski S, Menon V, Olah M
Acta Neuropathol
· 2025 Jul · PMID 40728732
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Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominan...Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.
Yokota O, Miki T, Nakashima-Yasuda H
… +9 more, Ishizu H, Haraguchi T, Miyashita A, Ikeuchi T, Hasegawa M, Nishikawa N, Takenoshita S, Terada S, Takaki M
Acta Neuropathol
· 2025 Jul · PMID 40715826
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Agrawal S, Yu L, Barnes LL
… +3 more, Bennett DA, Boyle PA, Schneider JA
Acta Neuropathol
· 2025 Jul · PMID 40705123
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Primary age-related tauopathy (PART) has been associated with milder degrees of cognitive impairment, but the role of PART-related tangles, from the hippocampus, nearby inferior temporal neocortex, and the role of co-exi...Primary age-related tauopathy (PART) has been associated with milder degrees of cognitive impairment, but the role of PART-related tangles, from the hippocampus, nearby inferior temporal neocortex, and the role of co-existing pathologies on cognitive decline are underappreciated. We used three harmonized community-based clinicopathologic studies to investigate the association of regional distributions of tangles and co-existing pathologies with cognitive decline. At autopsy, PART was defined by a Braak NFT stage of I-IV in the absence or with limited amyloid-β (Thal ≤ 2). Tau tangle density from the hippocampus and inferior temporal cortex were evaluated by AT8-immunohistochemistry. Other brain pathologies (LATE-NC, Lewy bodies (LBs), and vascular pathologies) were also evaluated. Linear mixed effect models were employed to examine the associations between regional tau tangles and other brain pathologies with decline in global cognition and 5 cognitive domains. Among 1,859 participants, 527 (28%) had neuropathologically confirmed PART: 385 had possible PART and 142 had definite PART, with an average age at death of 88 ± 6.9 years and 63% being female. Nearly all PART participants (N = 524) had hippocampal tangles and 449 also exhibited tangles in the inferior temporal neocortex. After controlling demographics and other brain pathologies, hippocampal and inferior temporal neocortical tangle burden were each associated with decline in global cognition and episodic memory; however, the effect of inferior temporal neocortical tangles on decline was 3.2 times stronger than that of hippocampal tangles. In further analyses, when included together in the same model, only the association of inferior temporal neocortical tangle burden persisted. However, using Braak staging alone, we did not find a clinical-pathological relationship between tangles and cognitive decline. Additionally, LATE-NC, LBs, atherosclerosis, and cerebral infarcts were each independently associated with cognitive decline. Our data also indicated that LATE-NC may have stronger impact on cognitive decline in PART than tau tangles. Overall, this study provides evidence that both extension of tangles to the nearby neocortex, specifically the inferior temporal, along with other co-pathologies, particularly LATE-NC, play a key role in cognitive decline in PART.
Extracellular amyloid plaques, the pathognomonic hallmark of Alzheimer's disease (AD), are also observed in cognitively unimpaired subjects in the preclinical stages. Progressive accumulation of fibrillar amyloid-β (Aβ)...Extracellular amyloid plaques, the pathognomonic hallmark of Alzheimer's disease (AD), are also observed in cognitively unimpaired subjects in the preclinical stages. Progressive accumulation of fibrillar amyloid-β (Aβ) as plaques and perivascular deposits occur two decades before clinical onset, making Aβ a long-lived peptide. To characterize the amyloid plaques biochemically, both the Aβ-load as well the post-translational modifications (PTMs) could serve as markers for distinguishing the pre-clinical stage compared to later prodromal and clinical stages of AD. Recently, we described the presence of extensive isomerization of the Aβ N-terminus in AD post-mortem brains that is significantly increased compared to the age-matched non-AD control brains with Aβ aggregates. In this report, we performed Lys-N enzymatic digestion followed by mass spectrometry-based quantitative analysis of the most common PTMs associated with plaque Aβ. We focused on pyroglutamation (pGlu3), citrullination (cit5), N-terminal truncation (Aβ), C-terminal isoforms (Aβ and Aβ), and isomerization of aspartic acid residues (Asp-1 and Asp-7) in postmortem human brain tissue from pathologically negative (no Aβ plaques) controls (n = 23), controls with Aβ plaques (n = 35), Parkinson's disease (PD) with (n = 28) and without Aβ accumulation/plaques (n = 30) and symptomatic AD (n = 60). The AD cases contained statistically significant amounts of Asp-1 and Asp-7 isomerized Aβ (~ 90%) compared to controls (preclinical AD) and PD brains with fibrillar Aβ aggregates/deposits. We find that the ratio of isomerized N-terminus Aβ (Aβ) species in the brain detergent soluble pool differentiates older fibrillar Aβ deposits in symptomatic AD brain compared to Aβ deposits detected in preclinical AD and PD. Citrullinated pGlu3-Aβ was increased only in symptomatic AD, highlighting this Aβ PTM is a unique feature of parenchymal plaques in advanced AD. Our results have implications for early therapeutic targeting of these modified species as well as potential for better biofluid biomarker development for drug efficacy monitoring.
Martinez-Perez DA, McGlothan JL, Rodichkin AN
… +5 more, Abilmouna K, Bursac Z, Lopera F, Villegas-Lanau CA, Guilarte TR
Acta Neuropathol
· 2025 Jul · PMID 40676304
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Translocator protein 18 kDA (TSPO) imaging using positron emission tomography (PET) is widely used to assess neuroinflammation in Alzheimer's disease (AD). However, the significance of the increase in brain TSPO levels i...Translocator protein 18 kDA (TSPO) imaging using positron emission tomography (PET) is widely used to assess neuroinflammation in Alzheimer's disease (AD). However, the significance of the increase in brain TSPO levels in AD pathophysiology is not known. Here, we show that in the 5XFAD transgenic mouse model, brain TSPO levels increase in an age-, brain region-, and sex-dependent fashion. TSPO levels were first increased in the subiculum at 1.5 months of age in male and female 5XFAD mice compared to wildtype mice. The TSPO increase in the subiculum of 1.5-month 5XFAD mice coincided with the appearance of Aβ aggregation and increased serum Aβ/Aβ ratio which occurred prior to increased serum neurofilament light chain (Nfl) levels and well before cognitive function deficits. We also discovered that the brain TSPO increase was driven by an expansion of activated microglia in contact with Aβ-plaques, that also expressed higher TSPO levels per microglia than microglia not in contact with plaques. While overall, astrocytes were highly activated, the increased TSPO signal in the 5XFAD mouse brain did not increase in astrocytes. We also compared the 5XFAD mouse findings to postmortem human brain tissue from early-onset autosomal-dominant Presenilin 1 (PSEN1)-E280A mutation AD cases. The results in PSEN1-E280A cases confirmed the 5XFAD mouse findings relevant to increased TSPO levels and an increase in TSPO per microglia contacting Aβ-plaques. In summary, TSPO is an early biomarker of neuroinflammation in the AD brain that first increases in the subiculum simultaneously with increased Aβ aggregation and serum Aβ/Aβ ratio. The increased TSPO response in the 5XFAD mouse brain and in the brain from PSEN1-E280A mutation AD cases reflects Aβ-plaque-associated microglia with a high TSPO content. This microglia subtype is likely to promote the progression of AD pathology, neurodegeneration, and cognitive decline and their high TSPO content may serve as a target for TSPO ligand-based therapy.
Sanchiz-Calvo M, Coccia E, Cawthorne C
… +11 more, Morrone Parfitt G, Torre-Muruzabal T, Tsafaras G, Van Laere K, Cabezudo D, Cascalho A, Van den Haute C, Vangheluwe P, Blanchard J, Bentea E, Baekelandt V
Acta Neuropathol
· 2025 Jul · PMID 40676227
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ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mu...ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson's disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson's disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Atp10b knockdown in rat brain induced parkinsonian motor deficits, and longitudinal striatal dopamine transporter F-FE-PE2I PET imaging revealed a progressive decrease in binding potential. Immunohistochemical analysis conducted one year post-injection confirmed the loss of dopaminergic terminals in the striatum, alongside a loss of dopaminergic neurons in the substantia nigra pars compacta. The expression of LAMP1, LAMP2a, cathepsin B and glucocerebrosidase was studied in dopaminergic neurons. A decrease in lysosomal numbers and an increase in lysosomal volume were observed more consistently in one of the knockdown constructs. The vulnerability of dopaminergic neurons to ATP10B loss-of-function was also observed in midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones, which showed a significant reduction in TH-positive neurons. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson's disease patients.
de Oliveira AP, Baghel D, Holcombe B
… +4 more, Chase W, Ward T, Wang SJ, Ghosh A
Acta Neuropathol
· 2025 Jul · PMID 40652435
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Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by amyloid-β (Aβ) deposition in blood vessel walls, leading to hemorrhage and recurring stroke. Despite significant overlap with Alzheimer's disease...Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by amyloid-β (Aβ) deposition in blood vessel walls, leading to hemorrhage and recurring stroke. Despite significant overlap with Alzheimer's disease (AD) through shared Aβ pathology, the specific structural characteristics of Aβ aggregates in CAA and their variations between stages of disease severity are yet to be fully understood. Traditional approaches relying on brain-derived fibrils can potentially overlook the polymorphic heterogeneity and chemical associations within vascular amyloids. This study utilizes sub-diffraction, label-free optical photothermal infrared (O-PTIR) spectroscopic imaging to directly probe the chemical structure and heterogeneity of vascular amyloid aggregates within human brain tissues across different CAA stages. Our results demonstrate a clear increase in β-sheet content within vascular Aβ deposits corresponding to disease progression. Crucially, we identify a significant presence of antiparallel β-sheet structures, particularly prevalent in moderate/severe CAA. The abundance of antiparallel structures correlates strongly with co-localized lipids, implicating a lipid-mediated aggregation mechanism. We substantiate the ex-vivo observations using nanoscale AFM-IR spectroscopy and demonstrate that Aβ40 aggregated in-vitro with brain-derived lipids adopts antiparallel structural distributions mirroring those found in CAA vascular lesions. This work provides critical insights into the structural distributions of Aβ aggregates in CAA, highlighting the presence of polymorphs typically associated with transient intermediates, which may lead to alternate mechanisms for neurotoxicity.
Mastrangelo A, Caldera S, Mastenbroek SE
… +14 more, Vittoriosi E, Janelidze S, Serrano GE, Atri A, Shill H, Driver-Dunckley E, Mehta S, Adler CH, Mammana A, Magliocchetti F, Baiardi S, Beach TG, Hansson O, Parchi P
Acta Neuropathol
· 2025 Jun · PMID 40549179
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The identification of biomarkers predicting the burden of brain alpha-synuclein (α-syn) pathology in vivo represents a research priority in Lewy body disease (LBD). Recently, some kinetic parameters of seed amplification...The identification of biomarkers predicting the burden of brain alpha-synuclein (α-syn) pathology in vivo represents a research priority in Lewy body disease (LBD). Recently, some kinetic parameters of seed amplification assays (SAAs) for α-syn showed associations with measures of clinical progression. However, preanalytical and analytical factors significantly affect these parameters, reducing reproducibility. The Endpoint Dilution (ED) SAA Real-time Quaking-induced Conversion (RT-QuIC) is emerging as an alternative, more accurate tool for seed quantification. Still, the approach needs validation in large patient cohorts. We applied the ED RT-QuIC to postmortem ventricular cerebrospinal fluid (CSF) samples from 357 brain donors, including 168 who showed LBD at neuropathologic examination. We estimated the seeding dose, yielding positive responses in 50% of replicate reactions (SD50), using the midSIN algorithm and correlated these values with postmortem synuclein pathology burden and clinical severity measures. LBD was staged through the Unified Staging System for Lewy Body Disorders and the Lewy pathology consensus criteria. The SD50 values (expressed in logSD/ml) differed significantly among participants at different LBD stages (p < 0.0001), with those at a neocortical stage demonstrating higher values than those at a brainstem-predominant stage (p < 0.0001). The SD50 values were significantly associated with the LBD load evaluated through immunohistochemistry (Rho = 0.62, p < 0.0001). Participants showing higher SD50 values performed worse at the last available scores on clinical scales evaluating motor (Rho = 0.33, p < 0.0001) and olfactory functions (Rho = - 0.33, p < 0.0001). The SD50 scores accurately distinguished neocortical LBD participants from those at lower stages (area under the curve, 0.86; 95% confidence interval, 0.79-0.92). The CSF ED RT-QuIC measure of α-syn seeds correlated significantly with LBD burden and clinical severity scores. These findings validate the CSF ED RT-QuIC as a quantitative assay for misfolded brain α-syn in LBD. This novel approach may be clinically applied to identify individuals at different stages of LBD pathology in research settings.