Murray, Melissa E.

Abstract Background Neurodegenerative tauopathies, characterized by the aggregation of misfolded tau protein, poses a significant clinical and scientific challenge. Tau interaction with other proteins affects the formation of ‘tau‐seed’ but less is known about its effects on tau‐seed properties. Our previous study revealed that Bassoon (BSN), a presynaptic protein, interacts with tau‐seed, exacerbating its toxicity. A parallel study also associated missense mutations in BSN with tau aggregation in patients, prompting an investigation into the influence of BSN and its mutations in neurodegeneration for potential therapeutic insights. Method We generated a knock‐in mouse model (BSNKI) harboring the disease‐associated p.Pro3866Ala mutation in endogenous Bsn. Cognitive and motor abilities were evaluated throughout the lifespan of heterozygous and homozygous BSNKI mice, along with analyses of BSN and tau patterns, gliosis, and gene expression changes in their brains. Additionally, we conducted single‐nucleic RNA sequencing to identify changes at the cellular level. Result BSNKI mice displayed progressive motor and memory impairments on the rotarod and fear conditioning assays, respectively. At 10 months, their brains displayed somatic BSN and pathological tau accumulation, with the gene expression changes indicating alterations of microglia, classical complement cascade, and synapse pruning pathways, as well as dysregulation of protein quality control pathways. Neuropathological data suggests that the BSN P3866A mutation instigates robust microglia activation, increased microglia‐mediated synapse engulfment, and a co‐deposition of proteasomal subunits with BSN. Furthermore, snRNA‐seq data suggest changes in neuronal populations and cell signaling. Conclusion Our BSNKI mouse model revealed the contributions of BSN P3866A mutation to tau pathogenesis and neurodegeneration. BSNKI animals displayed progressive motor and memory impairments, deposits of endogenous tau and BSN, as well as changes in gene expression and neuronal populations. Notably, BSN likely plays a dual role, promoting tau aggregation and sequestering protein degradation molecules, leading to tau and protein accumulation at the soma and synapse, which in turn could trigger neuroinflammation and other cellular changes. These findings propose BSN as a promising therapeutic target for tauopathies, underscoring the need for further exploration to elucidate underlying mechanisms and therapeutic implications.

Abstract Background Mitophagy constitutes a crucial cellular pathway in mitochondrial quality control, in which the enzymatic pair PINK1 and PRKN selectively decorates damaged mitochondria with phosphorylated‐ubiquitin (pS65‐Ub), facilitating their autophagic‐lysosomal removal. We previously demonstrated significant accumulation of pS65‐Ub labeled damaged mitochondria in Lewy body and Alzheimer’s disease autopsy brain. This mitophagy alteration was strongly associated with pre‐tangle tau pathology in neurons. The effects of distinct tau species on mitophagy across different cell types however remain largely unknown. We therefore expanded our analyses to primary tauopathies, exploring how specific tau forms and their aggregation influence mitophagy in selectively vulnerable brain regions and cell types. Method This study included 92 control and tauopathy cases with primary age‐related tauopathy (PART), Pick’s disease (PiD), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). Immunohistochemistry for the mitophagy marker pS65‐Ub and phospho‐tau was performed in vulnerable brain regions (hippocampus for PART and PiD, primary motor cortex for PSP and CBD). A deep learning‐based image identification model was used to identify and quantify distinct tau inclusions. pS65‐Ub‐positive cells were manually counted and grouped based on signal intensity and morphology. Immunofluorescence co‐staining of pS65‐Ub and phospho‐tau was conducted to study their spatial relationship at single‐cell level. Result We observed marked increases in pS65‐Ub‐positive cells in the hippocampus of PART and PiD cases compared to controls. Although less prominent, significant increases were also found in the primary motor cortex of PSP, whereas only minor changes were observed in CBD. Single‐cell analyses revealed that the accumulation of pS65‐Ub was most abundant in hippocampal neurons from PART. Cells with lower signal intensity contained mostly granular pS65‐Ub deposits, while those with higher intensity harbored rather vacuolar inclusions. Across tau aggregate subtypes, pS65‐Ub levels were strongly correlated and often co‐resided with neurofibrillary tangles and Pick bodies. Such correlations were weaker for coiled bodies and tufted astrocytes, and absent for astrocytic plaques. Conclusion Our study highlights distinct mitophagy alterations in primary tauopathies that are associated with specific tau inclusions in neurons, oligodendrocytes, and astrocytes. The observed pathological heterogeneity and complex mitophagy disruption underscores the need for future studies to elucidate pathogenic mechanisms and advance targeted therapeutics for each tauopathy.

Abstract Background Individual environmental exposures, the exposome, can play an influential role in the development and progression of neurodegenerative diseases such as AD. The protein components of the main AD neuropathologies, amyloid (Aβ) plaques and tau neurofibrillary tangles (NFTs), can be measured using immunohistochemical and biochemical approaches. The main genetic risk factor for AD is the APOE e4 allele. APOE levels can also be measured in the brain. We hypothesize that social determinants of health, specifically alcohol and tobacco consumption, and the area deprivation index (ADI), could play a considerable role in severity of neuropathology and brain biochemical phenotypes of AD. Method We evaluated 478 neuropathologically characterized AD donors, from the Mayo Clinic Brain Bank. 469 samples had available biochemical measures (APOE, Aβ40, Aβ42, tau, and phospho‐tau (Thr231)), collected across three isolated fractions (soluble (TBS), membrane‐bound (TX), and insoluble (FA)) of the superior temporal gyrus. Exposome variables were extracted from the available records. ADI from the Neighborhood Atlas® version from the year 2015 was obtained from de‐identified addresses. ADI, smoking and alcohol were available for 263 of these donors and were examined for association with biochemical measures using linear regression adjusting for age at death and sex. Result Higher ADI levels representing neighborhoods with increased deprivation, were nominally associated (β=0.006, p =0.01) with soluble levels of APOE. Alcohol consumption was associated with lower levels of membrane bound APOE (β=‐0.23, p =0.04). Analysis with neuropathological variables including CAA ( N =454), Braak ( N =454), Thal ( N =454), Hippocampal sclerosis ( N =453), Lewy bodies ( N =455) will also be performed. Conclusion Different components of the social exposome may impact levels of core AD proteins. Additional analyses in expanded cohorts to further explore the associations with neuropathology are ongoing. We expect that understanding how the social exposome impacts specific aspects of neurodegenerative diseases will provide key insights into underlying, potentially modifiable, mechanisms of disease.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer’s disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Objective Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α‐synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically‐defined series of LBD cases. Methods We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High‐resolution whole‐genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes. Results Our analysis identified 1 significant ( P < 3.43 × 10 −5 ) and 4 suggestive ( P < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA‐mediated immune mechanisms in disease progression and subtype differentiation. Specifically, HLA‐DPB1*06:01 was significantly associated with lower Lewy body counts in the parahippocampal gyrus ( P = 3.30 × 10 −5 ), with weaker and suggestive associations observed in the middle frontal ( P = 1.80 × 10 −4 ) and inferior parietal gyrus ( P = 6.33 × 10 −4 ). Additionally, although only suggestive, HLA‐DRB1*11:01 correlated with a lower Thal amyloid phase ( P = 1.56 x 10 −4 ), and HLA‐B*15:01 correlated with an increased risk of diffuse LBD ( P = 7.58 x 10 −4 ). Interpretation This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune‐related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492–501

Abstract Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical–pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease‐modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. Highlights We celebrate 40 years of NIA‐funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease‐modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.

Abstract INTRODUCTION Few African American (AA) donors have been included in post mortem Alzheimer's disease (AD) studies compared to European‐ancestry (EA) individuals. METHODS We generated transcriptome‐wide bulk pre‐frontal cortex (PFC) gene expression data from 125 AA donors with neuropathologically determined AD and 82 AA controls. RESULTS Transcriptome‐wide significant differential expression was observed with 482 genes. The most significant, ADAMTS2 , showed 1.52 times higher expression in AD cases ( p = 2.96x10 −8 ). Comparison of findings with those from a recent gene expression study of EA brain donors revealed substantial concordance, including ADAMTS2 . Other associations not observed in EA results may be especially relevant to AD risk in the AA population. Examination of AA AD GWAS‐implicated variants identified several expression quantitative trait loci. CONCLUSION This first large‐scale AA brain AD gene expression study identified many differentially expressed genes, including ADAMTS2 , and supports gene expression as a molecular pathway underlying the impact of several AA AD risk variants. Highlights We performed the largest African American brain tissue Alzheimer's disease (AD) gene expression study. Expression differences for 482 genes, notably ADAMTS2 , were study‐wide significant. Many significant differentially expressed genes are involved in energy metabolism. Several previously known AD‐associated variants in African Americans are eQTLs. These results advance knowledge of the genetic basis of AD in the AA population.

AbstractINTRODUCTIONIncreasing evidence indicates that α‐synuclein (αSYN) oligomers are toxic. We sought to determine whether αSYN oligomers were associated with faster cognitive decline in prospectively‐followed patients with dementia with Lewy bodies (DLB).METHODSEight autopsy‐confirmed patients with DLB were selected based on rapid or slow cognitive decline determined by the rate of change of Mini‐Mental State Examination (MMSE) scores. Quantitative neuropathologic analysis of αSYN oligomers, Lewy‐related pathology, phosphorylated tau, and amyloid‐β was conducted in hippocampal subfields (CA1‐4 and subiculum) and the entorhinal cortex.RESULTSDLB with rapid cognitive decline showed greater CA1 αSYN oligomer burden (p = 0.029) and tau burden (p = 0.029) than DLB with slow decline. The groups showed comparable burden of Lewy‐related pathology and amyloid‐β pathology in the hippocampal formation and entorhinal cortex.DISCUSSIONHippocampal accumulation of αSYN oligomers and phosphorylated tau is associated with rapid cognitive decline in DLB. Therapeutic strategies targeting αSYN oligomers warrant further investigation.Highlights Proximity ligation assay (PLA) and digital pathology for oligomer quantification. Abundant α‐synuclein (αSYN) oligomers in CA1 of patients with dementia with Lewy bodies (DLB) with rapid decline. First human brain study linking αSYN oligomers to cognitive trajectory. Potential therapeutic implications of targeting αSYN oligomers in DLB.