Acta Neuropathologica最新文献

The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer’s disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = − 20, 95% CI − 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < − 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = − 0.2, 95% CI − 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.

Alzheimer’s disease (AD) includes a defining hallmark that correlates most closely to cognitive decline, namely misfolded tau protein. However, the “upstream” etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain, proteoforms, and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequelae. We uncovered tau citrullination on multiple epitopes caused by peptidyl arginine deiminase (PAD) enzymes. PAD-induced citrullination irreversibly converts arginine residues to citrulline, producing a net loss of positive charge, elimination of pi–pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimer’s disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule-binding repeats domain (MBR), and C-terminal domain (C-term) on full-length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimer’s disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher pathological tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.

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.

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.

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.

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.