Lourenco GF, Torres-Pacheco ME, Fu Y
… +5 more, Li H, McCann H, Shepherd CE, Kril JJ, Halliday GM
Acta Neuropathol
· 2025 Dec · PMID 41340001
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Nucleolar disturbances have long been implicated in neurodegenerative diseases but, to date, aggregation and immobilization of proteins into nucleolar bodies have only been reported in vitro and in cell models, and only...Nucleolar disturbances have long been implicated in neurodegenerative diseases but, to date, aggregation and immobilization of proteins into nucleolar bodies have only been reported in vitro and in cell models, and only for amyloid β (Aβ). In model systems, these bodies have been shown to coordinate local nuclear protein synthesis with potential to seed diagnostic neuropathologies. Here we confirm the presence of nucleolar aggregates of amyloid nature in postmortem brain tissue from controls and patients with neurodegenerative pathologies and demonstrate the nucleolar sequestration of fibrillation-prone proteins associated with neurodegenerative diseases (Aβ, tau, α-synuclein, TDP-43, and FUS, but not prion or peptide repeats). We identified nucleolar bodies ranging from multiple small foci to a centralized, large amyloid aggresome, that appear to represent progressive stages of protein immobilization from liquid-like foci to the formation of nucleolar aggresomes. Neurons with nucleolar aggresomes were more vulnerable to neurodegeneration, decreasing in number with increasing duration of disease. Nucleolar aggresomes with phosphorylated tau correlated with increasing amounts of neuropathology, while phosphorylated TDP-43 in nucleolar aggresomes distinguished cases with limbic-predominant age-related TDP-43 encephalopathy. Nucleolar aggresomes containing α-synuclein occurred in a large proportion of aged controls with limited neuronal loss (potentially asserting neuroprotection). Other fibrillation-prone proteins were either absent (prion and peptide repeats) or found less commonly in nucleolar aggresomes (Aβ and FUS), and amyloidogenic nuclear proteins not screened in this study may also occur in nucleolar aggresomes. Our data do not support the concept that proteins in aggresomes seed diagnostic neuropathologies as there were no associations between their presence in nucleoli aggresomes and their cytoplasmic or extracellular accumulation. Assessment of neurons with and without phosphorylated tau or α-synuclein aggresomes showed that phosphorylated tau ameliorated the increased DNA levels found in AD. Collectively, our observations establish that nucleolar sequestration of amyloidogenic proteins is a common molecular mechanism in the brain, representing a novel contribution to the understanding of nucleolar protein aggregation in the context of neuroprotection and neurodegeneration during brain aging.
Hou X, Richardson T, Heckman MG
… +6 more, Fiesel FC, White LJ, Koga S, Ross OA, Dickson DW, Springer W
Acta Neuropathol
· 2025 Dec · PMID 41326741
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The kinase-ligase pair PINK1-PRKN initiates mitophagy by recognizing and selectively tagging worn-out and dysfunctional mitochondria with phosphorylated ubiquitin (pS65-Ub) to facilitate their elimination via autophagy....The kinase-ligase pair PINK1-PRKN initiates mitophagy by recognizing and selectively tagging worn-out and dysfunctional mitochondria with phosphorylated ubiquitin (pS65-Ub) to facilitate their elimination via autophagy. In human autopsy brains, the number of pS65-Ub positive cells increases with age but is also associated with Lewy body (LB), neurofibrillary tangles (NFT), and senile plaque (SP) burden. Through a recent genome-wide association study, we identified two genetic modifiers of pS65-Ub levels, APOE4 and ZMIZ1 rs6480922. While LB, NFT, and SP pathologies often coexist in Lewy body dementia (LBD), it is unclear how genetic factors and comorbid neuropathologies interact to impact mitophagy in vulnerable brain regions. We therefore measured levels of the age and disease marker pS65-Ub in the hippocampus and amygdala of 371 LBD cases. Significant and independent associations with pS65-Ub levels were observed for each of the three pathologies LB, NFT, and SP in both regions, and the presence of APOE4 significantly strengthened the association between NFT and pS65-Ub in the hippocampus. While no interaction between LB and SP pathologies was observed regarding association with pS65-Ub, a significant interaction between LB and NFT pathologies on pS65-Ub accumulation was found in the amygdala, which was primarily observed in carriers of the minor allele of ZMIZ1 rs6480922. In summary, our study revealed complex interactions between LB pathology, NFT pathology, and genetic mitophagy modifiers in LBD brains, highlighting potential convergent molecular mechanisms underlying α-synuclein- and tau-associated mitophagy alterations.
Hinz FE, Friedel D, Ippen FM
… +37 more, Sill M, Korshunov A, Schweizer L, Schrimpf D, Göbel K, Friedrich LS, Aras FK, Bogumil H, Banan R, Dohmen H, Acker T, Brandner S, Schmid S, Capper D, Grassl N, Boldt HB, Wesseling P, Maas SLN, Martinez JPG, Stadelmann C, Reifenberger G, Stehle T, Barrantes-Freer A, Juratli TA, Pusch S, Haag D, Reuss DE, Herold-Mende C, Krieg S, Wick W, Etminan N, Platten M, Pfister SM, Jones DTW, Sahm F, von Deimling A, Suwala AK
Acta Neuropathol
· 2025 Nov · PMID 41299137
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Ioannou K, Perrin RJ, Abdullaieva K
… +7 more, Bluma M, Leuzy A, Poulakis K, Religa D, Rodriguez-Vieitez E, Chiotis K, Alzheimer’s Disease Neuroimaging Initiative
Acta Neuropathol
· 2025 Nov · PMID 41298940
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CSF Aβ reflects Alzheimer's disease neuropathologic change (ADNC), while CSF p-tau offers an indirect indication of tangle pathology. However, interpretation can be challenging when cognitive impairment is present alongs...CSF Aβ reflects Alzheimer's disease neuropathologic change (ADNC), while CSF p-tau offers an indirect indication of tangle pathology. However, interpretation can be challenging when cognitive impairment is present alongside Aβ positivity (Α +) but p-tau negativity (T -). We examined neuropathologic differences between CSF A + T - and A + T + profiles, defined by CSF Aβ42 and p-tau181 levels, hypothesizing that cognitively impaired older adults with a CSF A + T - profile would exhibit a greater co-pathology burden, suggesting alternative contributing disease processes. We identified 77 ADNI participants with available CSF biomarkers and neuropathologic assessments (median age = 79.8 years; IQR = 74.7-84.5). Depending on the presence-alone or in combination-of ADNC intermediate/high and non-ADNC pathologies (e.g., Lewy bodies (LB), argyrophilic grain disease (AGD), limbic-predominant age-related TDP-43 encephalopathy-neuropathologic change (LATE-NC)), individuals were classified as ADNC dominant, mixed ADNC, or non-ADNC dominant. The two CSF A + profiles were similar in demographics, frequency of cognitive impairment, longitudinal cognitive performance, clinical comorbidities, CSF Aβ42 levels, CSF α-synuclein positivity rates, and Aβ PET burden. ADNC intermediate/high was significantly more frequent in the CSF A + T + profile than in the CSF A + T - profile (100% vs. 78%, p value = 0.008). The most common co-pathologies contributing to cognitive impairment in the CSF A + T - profile were LATE-NC (stages 2-3) (47%), LB limbic/neocortical (44%), and AGD (stages II-III) (33%), while in the CSF A + T + profile, LB limbic/neocortical (28%) and LATE-NC (stages 2-3) (22%) predominated. The CSF A + T - profile showed 17% ADNC dominant, 61% mixed ADNC, and 22% non-ADNC dominant pathology, whereas the CSF A + T + profile showed 51% ADNC dominant and 49% mixed ADNC pathology (p = 0.001). Within the mixed ADNC subgroup, individuals with a CSF A + T - profile more often exhibited two or more non-ADNC co-pathologies compared to those with a CSF A + T + profile (73% vs. 21%, p = 0.009). Despite clinical similarities among cognitively impaired individuals with CSF A + T - and A + T + profiles, the CSF A + T - profile may reflect a greater burden of non-ADNC pathology. Extending biomarker profiling beyond Aβ and tau may facilitate more personalized care.
Hartman S, Aytan N, Nicks R
… +17 more, Hawkins S, Cherry J, Alvarez VE, Meng G, Tripodis Y, Martin B, Palmisano J, Goldstein LE, Katz DI, Dwyer B, Daneshvar DH, Crary JF, Alosco M, Xia W, McKee AC, Mez J, Stein TD
Acta Neuropathol
· 2025 Nov · PMID 41264095
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Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic va...Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common Transmembrane Protein 106B (TMEM106B) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether TMEM106B alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype (rs3173615). We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between TMEM106B risk and CTE presence, CTE stage, TDP-43, and dementia in those < = 65 and > 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by TMEM106B genotype. Among donors > 65 years old, the TMEM106B risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183-6.383], p = 0.019), comparable to the effect of playing > 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278-10.422], p = 0.016). In donors < = 65, TMEM106B risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015-23.705], p = 0.002). TMEM106B gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 (p's < 0.05), and TNF-α was negatively associated with cortical tau (p = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the TMEM106B risk genotype in CTE. Overall, TMEM106B rs3173615 is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.
Ghayal NB, Crook RJ, Jain A
… +12 more, Sachdeva G, Jiang P, Roemer SF, Sekiya H, DeTure MA, Baker MC, De Coster W, Oskarsson B, Josephs KA, Rademakers R, van Blitterswijk MM, Dickson DW
Acta Neuropathol
· 2025 Nov · PMID 41225259
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Aggregation of TAR-DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor...Aggregation of TAR-DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases diagnosed with a primary TDP-43 proteinopathy, including FTLD-TDP, FTLD-MND, and MND-TDP. Cases with FTLD-MND and MND-TDP were classified further into PLS, ALS, and PMA based on the relative loss of upper and lower motor neurons. ANXA11 proteinopathy was present in over 40% of FTLD-MND cases. Further, ANXA11 colocalized with TDP-43 in the pathologic inclusions of all FTLD-TDP type C cases, as well as 38 out of 40 FTLD-PLS cases (95%), of which 84% had TDP type B or an unclassifiable TDP-43 proteinopathy and 16% had TDP type C. Genetic analysis excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated two novel ANXA11 proteinopathies strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship between TDP-43 and ANXA11 in neurodegenerative disease, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises a distinct group of molecular pathologies and define three TAP types based on key clinical and neuropathologic characteristics.
Tsafaras G, Cabezudo D, Wetzels L
… +7 more, Tsakogias I, Abey A, Bentea E, Sanchiz-Calvo M, Van den Haute C, Wade-Martins R, Baekelandt V
Acta Neuropathol
· 2025 Nov · PMID 41217513
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Aggregated α-synuclein (αSyn) is a pathological hallmark of Parkinson's disease (PD), yet other protein aggregates, including tau, are commonly observed in PD brains. This suggests that PD is not solely a synucleinopathy...Aggregated α-synuclein (αSyn) is a pathological hallmark of Parkinson's disease (PD), yet other protein aggregates, including tau, are commonly observed in PD brains. This suggests that PD is not solely a synucleinopathy but may involve multiple, coexisting proteinopathies. Mutations in LRRK2, particularly the G2019S (GS), are the most common cause of familial PD. LRRK2-PD has been associated with both αSyn and tau pathology; however the mechanistic links between LRRK2 dysfunction and protein aggregation remain incompletely defined. Here we opted to investigate whether LRRK2 contributes to αSyn and tau pathology through common molecular pathways or via distinct cellular mechanisms. Viral vector-mediated αSyn overexpression in GS LRRK2 knock-in mice led to enhanced dopaminergic neurodegeneration, increased phosphorylated αSyn levels, pronounced neuroinflammation, and accumulation of lysosomal proteins, suggesting impaired αSyn clearance and immune activation as key drivers. Human iPSC-derived dopaminergic neurons from GS LRRK2 PD patients mirrored these findings. In contrast viral vector-mediated overexpression of tau in GS LRRK2 knock-in mice promoted tau phosphorylation but did not significantly affect neuroinflammation, lysosomal markers, or neurodegeneration, indicating a primarily cell-autonomous mechanism. Our results reveal a mechanistic divergence in how GS LRRK2 impacts αSyn and tau pathologies, supporting the notion that LRRK2 kinase activity contributes to PD pathogenesis through different pathways, thereby highlighting its potential as a therapeutic target in both familial and sporadic PD.
Acta Neuropathol
· 2025 Nov · PMID 41206373
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In synucleinopathies, the protein α-synuclein misfolds into Lewy bodies (LBs) in patients with Lewy body disease (LBD) or into glial cytoplasmic inclusions (GCIs) in patients with multiple system atrophy (MSA). The abili...In synucleinopathies, the protein α-synuclein misfolds into Lewy bodies (LBs) in patients with Lewy body disease (LBD) or into glial cytoplasmic inclusions (GCIs) in patients with multiple system atrophy (MSA). The ability of a single misfolded protein to cause disparate diseases is explained by the prion strain hypothesis, which argues that protein conformation is a major determinant of disease. We recently reported the unexpected finding of a novel α-synuclein strain in a Parkinson's disease with dementia patient sample containing GCI-like co-pathology along with widespread LB pathology, which led us to question if two α-synuclein strains can interact with one another in a patient and, if so, can strain competition occur. To test this possibility, we used the strain interference model developed in the prion field, in which a slower replicating strain-in this study, mouse-passaged MSA-is used to compete with a faster replicating strain-here, recombinant preformed fibrils (PFFs)-following sciatic nerve (sc.n.) inoculation. Unexpectedly, we found that PFFs generated using the same method differed in their ability to neuroinvade following sc.n. inoculation based on α-synuclein monomer source. Using a PFF preparation that does spread from the periphery, we conducted strain competition studies by first injecting TgM83 mice with mouse-passaged MSA into the sc.n. followed by a second injection with PFFs at 30, 45, and 60% of the MSA incubation period. We found that the two α-synuclein strains exhibited a synergistic effect during neuroinvasion, which was characterized by a decrease in incubation period along with evidence of the mouse-passaged MSA strain in the brain of terminal animals. These findings indicate that two α-synuclein strains can synergize with one another to accelerate the progression of clinical disease, representing a novel outcome in mixed infection studies.
Phuong HT, Tomas RF, Akmese C
… +18 more, Mijares A, Gerstin IM, Guo S, Bell LR, Ellwood R, Yegorova S, Ng SK, Massey G, Phillips J, Melloni A, Pletnikova O, Lou X, Clark HB, Troncoso JC, Hyman BT, Prokop S, Ranum LPW, Nguyen L
Acta Neuropathol
· 2025 Nov · PMID 41204969
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Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of pr...Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in ~ 60% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining. In addition to ADNC, a subset of polyGR+ aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+ aggregate levels are ~ 3.8- and ~ 3.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+ proteins produced by the CASP8 GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by CASP8 polyGR+ protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.
Hill E, Patel MM, Ribes JM
… +20 more, Linehan J, Zhang F, Jakubcova T, Hamdan S, Tomlinson A, Ercolani T, Schmidt C, Ahmed P, Thirlway G, Argentina F, Marinho AT, Jones E, Kaye N, Fitzhugh C, Jackson GS, Brandner S, Klöhn PC, Collinge J, Cunningham TJ, Mead S
Acta Neuropathol
· 2025 Nov · PMID 41186731
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Increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed genetic risk mechanism for sporadic prion disease and progressive supranuclear palsy, as well as being impl...Increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed genetic risk mechanism for sporadic prion disease and progressive supranuclear palsy, as well as being implicated in Alzheimer's disease. However, no study has validated its functional role in prion disease, its mechanism of action nor explored the disease stage at which it is acting. Here, we show that syntaxin-6 knockdown in cellular models increases cell-associated infectivity, whilst overexpression produces the opposite effect. This observation is broadly consistent across multiple cell types and prion strains. Furthermore, syntaxin-6 knockdown leads to an accumulation of perinuclear disease-related PrP, consistent with a trafficking mechanism, and alters the morphology of disease-related PrP. We demonstrate that syntaxin-6 knockdown reduces the secretion of prions from infected cells, which provides a mechanism for the prion-related cellular phenotypes observed. Complementary in vivo studies showed that syntaxin-6 influences early stages of prion disease in experimental mice, increasing transmission risk after inoculation with low prion doses. Conversely, syntaxin-6 does not affect prion propagation kinetics or toxicity during established disease. Taken together, our studies firmly establish syntaxin-6 as a modifier of prion pathogenesis with a role in prion trafficking and export. Our findings further suggest that syntaxin-6 modifies the risk of the establishment of disease in line with its genetic association in humans. Thus, this work provides important insights into the role of a pleiotropic prion/prion-like modifier, grounded in human genetics evidence, which may have wider relevance to other neurodegenerative diseases.
Smith BC, Chomyk A, Habean ML
… +4 more, Shaw BC, Tinkey RA, Trapp BD, Williams JL
Acta Neuropathol
· 2025 Nov · PMID 41175293
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Chronic active lesions are a manifestation of multiple sclerosis (MS) and have been associated with disease progression. While astrocytes are heavily implicated in MS, little is known about their role in lesions, particu...Chronic active lesions are a manifestation of multiple sclerosis (MS) and have been associated with disease progression. While astrocytes are heavily implicated in MS, little is known about their role in lesions, particularly in the lesion core. Here, we sought to gain insight into the spatial relationship between astrocytes and defined regions of chronic active lesions, and to better understand the environment within the relatively understudied lesion core, an area primarily composed of astrocytes. We analyzed four defined protein panels, focusing on astrocytes, in postmortem fresh-frozen cortical white matter tissue using NanoString GeoMx spatial protein profiling to compare normal appearing white matter (NAWM), the chronic active perilesion, rim, and core. We then performed immunofluorescent microscopy to determine the localization patterns of identified proteins within astrocytes. The most significant differences were observed between the chronic active lesion core and both NAWM and the perilesion. Proteins upregulated in the core relative to NAWM or the perilesion included the MAPK signaling pathway, immune checkpoint proteins, and indicators of phagocytosis. Our data indicate that astrocytes in the lesion core are distinct and actively influence the microenvironment. We posit that the differentially upregulated astrocytic signaling pathways, namely MAPK, immune checkpoints, and debris engulfment, are indicative of reactive astrocytes providing support to demyelinated axons by tempering the inflammatory milieu and clearing debris within the lesion core.
Neubauer A, Weissenbrunner D, Pekrun S
… +5 more, Roeber S, Ruf V, Feyen P, Strübing FL, Herms J
Acta Neuropathol
· 2025 Oct · PMID 41165827
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Alpha-synuclein (α-syn) deposits are common in around half of the Alzheimer's disease (AD) cases. While direct and indirect protein interactions are suggested, the relationships between different protein aggregates remai...Alpha-synuclein (α-syn) deposits are common in around half of the Alzheimer's disease (AD) cases. While direct and indirect protein interactions are suggested, the relationships between different protein aggregates remain poorly understood. Here, we aimed to characterize α-syn, amyloid beta (Aβ), and tau load distributions of AD patients. Protein deposits were automatically quantified with random forest pixel classifiers in immunohistochemical stains of up to 28 brain regions in 72 brains with advanced AD neuropathological change. α-syn-negative cases were distinguished from amygdala predominant, brainstem predominant, and cortical α-syn-positive cases. Relationships with age, sex, and ApoE genotype were examined. α-syn co-pathology was detected in 60% of AD cases, more frequently, although not significantly, in women. Half of these positive cases presented α-syn deposits in the cortex, around one-third predominantly in the amygdala, and the remaining cases primarily in the brainstem. A high α-syn load in the amygdala was associated with an increased cortical Aβ load. The cortical tau load was increased in the amygdala-predominant α-syn group, but decreased in the brainstem-predominant and cortical α-syn cases in comparison with α-syn-negative cases. ApoE4 was associated with higher hippocampal α-syn and cortical Aβ deposition. Younger age at death was associated with a focally higher Aβ and tau load. AD cases with cortical α-syn deposition tended to have a younger age at death. Here, we show that next to age, sex, and ApoE genotype, the α-syn distribution in AD is related to different Aβ and tau loads. This may have therapeutic relevance for identifying patients who respond to Aβ immunotherapy related to tau burden and underpin the need to define α-syn pathology and distribution in early disease stages.
Zhang Z, Capuano AW, Beadell A
… +7 more, Tasaki S, Cui X, Mehta RI, Bennett DA, He C, Zhang W, Arvanitakis Z
Acta Neuropathol
· 2025 Oct · PMID 41148349
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BACKGROUND: Cytosine modifications play critical roles in gene regulation and disease pathogenesis. Elucidating novel epigenetic contributions to Alzheimer's disease (AD) could advance diagnostic, prognostic, and therape...BACKGROUND: Cytosine modifications play critical roles in gene regulation and disease pathogenesis. Elucidating novel epigenetic contributions to Alzheimer's disease (AD) could advance diagnostic, prognostic, and therapeutic strategies. 5-hydroxymethylcytosine (5hmC), a stable and dynamic DNA modification, has emerging links to AD pathophysiology and potential uses as a biomarker. Cognitive decline, a hallmark of AD progression, varies across individuals and is not fully explained by classic pathological markers. Here, we aimed to develop and validate brain-derived 5hmC-based epigenetic scores to distinguish AD from non-AD pathology and examine their relationship to individual cognitive trajectories. METHODS: Genome-wide 5hmC profiles were generated using 5hmC-Seal and next-generation sequencing on 1016 postmortem human brain prefrontal cortex samples from well-characterized, deceased participants in a longitudinal, clinical-pathologic research study on aging. Samples were processed in independent training and validation sets. Genomic features (e.g., gene bodies, enhancers) were summarized, followed by differential analysis and machine learning-based feature selection to construct classification models distinguishing AD from non-AD. RESULTS: After quality control and batch correction of 5hmC data, 1005 participants were included, with 655 classified as having AD and 350 as non-AD, according to NIA-AA neuropathologic criteria. In the training set (n = 859), 136 candidate gene bodies and 96 enhancers were selected based on variability and relaxed significance thresholds (p < 0.1). Pathway enrichment analyses implicated cardiovascular function, endocytosis, and MAPK signaling pathways. Using these features, we developed machine learning models that distinguished AD from non-AD with high performance in both the training set (AUC = 87.0%; 95% CI 84.2-89.7%) and validation set (n = 146; AUC = 91.4%; 95% CI 86.6-96.2%). Moreover, the resulting AD-score was significantly associated with rates of global and five domain-specific cognitive decline. CONCLUSION: This study extends prior work by translating brain 5hmC profiles into epigenetic scores that distinguish AD pathology and reflect individual cognitive trajectories. These findings highlight the potential of brain-derived 5hmC modifications as biomarkers for AD and as tools to advance research on disease progression, offering a new direction for epigenetics-informed clinical applications in AD.
Buck SA, Malankhanova T, Strader S
… +9 more, Ma EB, Yim S, Pratt HW, Ervin J, Lee EB, Wang SJ, Cohen TJ, West AB, Sanders LH
Acta Neuropathol
· 2025 Oct · PMID 41128923
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Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated...Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12 and Rab10. Rab12 and Rab10 are expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment, and lysosomal stress activates LRRK2 phosphorylation of Rabs. In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases. Analysis of brain tissue lysates and immunohistochemistry of pathology-susceptible brain regions demonstrate that pS106-Rab12 levels are increased in Alzheimer's disease (AD) and Lewy body disease (LBD), including PD with and without G2019S LRRK2 mutation. At early pathological stages, phosphorylated Rab12 localizes to granulovacuolar degeneration bodies (GVBs), which are thought to be active lysosomal-like structures, in neurons. pS106-Rab12-positive GVBs accumulate with pathological tau across brain tissues in AD and LBD, and in G2019S LRRK2 mutation carriers. In a mouse model of tauopathy, pS106-Rab12 localizes to GVBs during early tau deposition in an age-dependent manner. While GVBs are largely absent in neurons with mature protein pathology, subsets of both tau and α-synuclein inclusions appear to incorporate pS106-Rab12 at later pathological stages. Further, pS106-Rab12 labels GVBs in neurons and shows co-pathology with tau inclusions in primary tauopathies including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Finally, pT73-Rab10 is elevated and localizes to GVBs, but not tau and α-synuclein inclusions, in AD and LBD, including G2019S LRRK2 mutation carriers. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.
Augur ZM, Fogo GM, Arbery MR
… +8 more, Hsieh YC, Rao NR, Goyal K, Dexter E, Bennett DA, Savas JN, Stern AM, Young-Pearse TL
Acta Neuropathol
· 2025 Oct · PMID 41085772
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The autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) are the primary protein degradative mechanisms maintaining proteostasis in neurons. However, the impact of human genetic variation on these p...The autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) are the primary protein degradative mechanisms maintaining proteostasis in neurons. However, the impact of human genetic variation on these pathways and the role of BAG3 are poorly understood, particularly in the context of Alzheimer's disease, where proteostatic dysfunction is a defining hallmark. We utilized a large panel of iPSCs from deeply phenotyped cohorts to interrogate genetic contributions to baseline autophagic flux and UPS activity in human neurons, and protein turnover was assessed using SILAC-based quantitative proteomics. Across this panel of neurons, we observed substantial inter-individual differences in autophagic flux, which was inversely correlated with UPS activity. This reciprocal relationship extended to tau homeostasis, where higher autophagic flux resulted in reduced accumulation of aggregated, phosphorylated tau. Proteomic analyses revealed that global protein turnover dynamics stratified based on degradation pathway activity and could predict pathway-specific substrate dependencies. Interestingly, Bcl-2-associated athanogene 3 (BAG3), an important member of the chaperone-assisted selective autophagy pathway, emerged as a dynamically regulated autophagy chaperone, responsive to pharmacological inhibition of both the UPS and ALP. BAG3 knockout in neurons decreased autophagic flux and increased levels of high-molecular-weight phosphorylated tau. Notably, familial AD mutations and Aβ exposure induced BAG3 expression in neurons, while elevated BAG3 levels in human brain tissue were associated with higher neuropathological burden and disease progression. Our findings identify BAG3 as a key modulator of proteostasis in human neurons. Its regulation across genetic backgrounds and pathological stimuli suggests a central role in maintaining degradation activities in Alzheimer's disease and related disorders.
Pfaff E, Schramm K, Blattner-Johnson M
… +30 more, Jones BC, Stark S, Balasubramanian GP, Previti C, Autry RJ, Fiesel P, Sahm F, Reuss D, von Deimling A, van Tilburg CM, Pajtler KW, Milde T, Dirksen U, Kramm CM, von Bueren AO, Hutter C, de Wilde B, Molenaar J, Gerber NU, Lohi O, Munthe-Kaas MC, Georgantzi K, Kazanowska B, Zápotocký M, Kattamis A, Filippidou M, Fried I, Pfister SM, Witt O, Jones DTW
Acta Neuropathol
· 2025 Oct · PMID 41076459
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Diffuse midline glioma (DMG; a subtype of pediatric high-grade glioma) is a fatal disease in children, due to the localization in critical structures of the central nervous system, its invasive nature, and limited treatm...Diffuse midline glioma (DMG; a subtype of pediatric high-grade glioma) is a fatal disease in children, due to the localization in critical structures of the central nervous system, its invasive nature, and limited treatment options. Molecularly, DMG with loss of histone 3 K27 trimethylation (mostly through the typical K27M-mutation in histone 3) have been relatively well characterized, however, no unambiguous Achilles' heel for targeted therapeutic approaches could be identified to date. This study integrates detailed molecular characteristics of pediatric DMGs with clinical data in a large, international cohort in order to contribute to a better understanding necessary for further development of therapeutic approaches. A total of 162 DMG tumors were analyzed within the INFORM registry from 01/2015 to 11/2023 using comprehensive molecular profiling (including exome, whole-genome and RNA next-generation sequencing approaches, complemented with DNA methylation analysis). Molecular results were correlated with clinical data of the respective patients including the treatment regimen applied and patients' outcomes. This well-defined cohort of histone 3 K27-altered DMG according to the current WHO classification showed typical molecular alterations for this entity, with differences in frequencies in specific subgroups. The presence of TP53 mutation and the absence of MAPK pathway alteration in the tumors were associated with worse outcomes. In a substantial proportion of patients, genetic alterations serving as targets for potential therapeutic approaches could be identified. This large, international, prospective DMG cohort combines comprehensive molecular characterization of the tumors with registry-level clinical data, thereby contributing to a better understanding of the underlying tumor biology, potential prognostic and predictive markers and the potential impact of targeted therapies.
Richardson TE, Walker JM, Farrell K
… +3 more, Oliveira TG, White CL, Crary JF
Acta Neuropathol
· 2025 Oct · PMID 41065841
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Primary age-related tauopathy (PART) was proposed in 2014 as a neuropathological term to describe patients with Alzheimer's-type medial temporal lobe neurofibrillary degeneration in the absence of significant β-amyloid p...Primary age-related tauopathy (PART) was proposed in 2014 as a neuropathological term to describe patients with Alzheimer's-type medial temporal lobe neurofibrillary degeneration in the absence of significant β-amyloid pathology. Over the past decade, this designation has gained widespread adoption, helping to clarify the interpretation of biomarker profiles, delineate early-stage tauopathy in aging, and differentiate non-Alzheimer tauopathies from aging and classical Alzheimer disease. This review revisits PART ten years following its conception, critically evaluating its neuropathological features, clinical correlates, molecular underpinnings, and current limitations. We synthesize recent advances in neuroimaging, biomarkers, genetics, and epidemiology, explore the relationship between PART and other age-associated neurodegenerative processes, and propose revisions to the original PART criteria. While PART has served as a valuable framework for studying tau pathology in aging, key questions remain regarding its pathogenesis, clinical significance, and relationship to the broader spectrum of tauopathies. We highlight major gaps in knowledge and outline priorities for future research aimed at defining the mechanisms, biomarkers, and clinical criteria that will determine whether PART represents a distinct disease or a universal feature of human brain aging.