2026-08-11 | Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
Open article ↗
2026-08-07 | Molecular Disease Stages of Oligodendrocytic and Neuronal Tau Burden in Progressive Supranuclear Palsy
Abstract Background Progressive supranuclear palsy (PSP) is a primary tauopathy defined by the accumulation of 4R tau isoforms in neurons, oligodendrocytes and astrocytes. Despite evidence of genetic susceptibility operating through glial cell types, it remains poorly understood how cell type-specific epigenetic-transcriptional programs evolve with progression of tau pathology. Methods We conducted single-nucleus chromatin accessibility (snATACseq) and RNA sequencing (snRNAseq) on postmortem frontal cortex samples from PSP patients (n = 8) and matched controls (n = 8), yielding over 144,000 nuclei passing quality control. Tau pathology burden, including neurofibrillary tangles, coiled bodies, and tufted astrocytes, was quantified on AT8-immunostained sections from the same individuals. We integrated differential gene expression analysis, transcription factor motif enrichment, weighted gene co-expression network analysis, and pseudotime modeling anchored to cell type-specific tau pathology burden to delineate molecular pseudo-progression trajectories. Results In eight cell types, 20 subclasses, and 70 subclusters, PSP brains displayed a selective depletion of certain excitatory deep-layer neurons and oligodendrocyte subclusters, with relative preservation of inhibitory neurons and vascular cells. Genetic risk enrichment was localized to astrocytes and oligodendrocytes, whereas excitatory neurons exhibited the greatest transcriptional dysregulation. Oligodendrocyte pseudo-progression indicated a transition from homeostatic myelination programs ( MBP, MOBP ) through glucocorticoid-responsive stress ( FKBP5 , ZBTB16 ), to compensatory myelination ( PLP1, CNP ) and proteostasis stress ( UCHL1, CYRAB, CLU ). Neuronal pseudo- progression revealed early dysregulation of synaptic ( RORB2, NRG3, NPTX1 ), microtubule dynamics ( KIF2C, RAB27B, TUBA/B ), and survival ( MEG3, FTX ) pathways, alongside a transient increase in neuron-glia interactions ( GRIP, CNTNAP4, ERBB4 ), converging late on ribosomal translation and vesicular trafficking modules across all neuronal subtypes. Cross-modal integration with independent cerebrospinal fluid proteomics identified a concordant subset of glial reactivity, axonal injury, and synaptic markers jointly dysregulated in inhibitory neurons, oligodendrocytes, and excitatory deep-layer neurons. Conclusion PSP pathogenesis reflects a combination of glial genetic susceptibility and staged, cell type-specific transcriptional dysfunction. Oligodendrocytes transition from myelination-competent states to FKBP5 -mediated stress states, while neurons show variably timed loss of synaptic excitability and survival programs, preceded by neuron-glia interactions and followed by convergent ribosomal-proteostatic failure. These cytopathology-anchored trajectories outline a potential pathophysiological sequence and may inform candidate selection for stage-specific therapeutic interventions in PSP.
Open article ↗
2026-07-21 | Microvascular pathology of proteotoxic endothelial signature characterizes Progressive Supranuclear Palsy
Abstract Cerebrovascular pathology is increasingly implicated in neurodegenerative diseases, yet its pathomechanistic contribution remains poorly defined. Building on prior evidence of dysregulated iron and oxygen homeostasis in early-affected brain regions of progressive supranuclear palsy (PSP), we hypothesized that brain microvascular alterations may play an etiological role in select neurodegenerative proteinopathies. First, we conducted a systematic neuropathological evaluation of 178 brains from the University Health Network Neurodegenerative Brain Collection, including Alzheimer’s disease-related neuropathologic change (ADNC; n=30), Lewy body disease with high or intermediate ADNC (n=38) and low ADNC (n=16), multiple system atrophy (MSA; n=14), PSP (n=39), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP; n=10), and controls (n=31). Arteriolosclerosis, microinfarction, and calcification were assessed in the basal ganglia and frontal cortex. Iron burden was correlated by quantification of Perl’s staining in MSA and PSP, where vessel pathology was most severe. Single-nucleus RNA-sequencing (snRNA-seq) of frontal cortex tissue from control (n=5) and PSP (n=8) cases with varying arteriolosclerosis severity was performed to characterize the vascular transcriptome, with validation against an independent snRNA-seq evaluation of PSP (n= 11), Pick’s disease (n=9), AD (n=10), and control (n=10) brains. Histological analysis revealed disease-specific involvement of microvascular pathology in neurodegenerative diseases, identifying PSP to demonstrate most prominent and widespread vessel wall thickening across regions examined. Regression analysis using demographic, APOE and MAPT genetic risk status, and neuropathological features of cases corroborated the distinct association with PSP pathology. Elevated iron load in early affected regions of MSA and PSP brains correlated with greater vessel wall thickening, suggesting a possible pathomechanistic relationship between the two disease physiologies. snRNA-seq analysis of vascular transcriptome identified robust upregulation of heat shock proteins and hypoxia-related genes in PSP endothelial cells and pericytes across both datasets. Importantly, we found the proteotoxic signature to be strongly associated with higher vessel scores in PSP cases, linking microvascular morphology to endothelial dysfunction. Our comprehensive neuropathological evaluation coupled with correlative snRNA-seq analysis establish PSP-specific arteriolar thickening associated with endothelial proteotoxic state as a candidate pathogenic mechanism. The cerebral arteriolar unit represents a compelling therapeutic target for disease modification in PSP.
Open article ↗
2026-07-04 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.
Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women's significant improvements in total raw score, letter-number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.
Open article ↗
2026-07-03 | Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer's Disease and Primary Tauopathies.
Cerebrovascular alterations are widely observed in both Alzheimer's Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Pick's disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.
Open article ↗
