Biology subjects

Woltjer, R. L.

Publications and source records attributed to Woltjer, R. L..

8 recordsLinked to original sources

bioRxiv2026

Stroke and Alzheimer's disease have distinct consequences on neurovascular function but synergize to increase amyloid deposition

INTRODUCTION: We examined whether stroke induces chronic cerebrovascular dysfunction and thereby exacerbates A{beta} pathology. METHODS: We exposed Tg2576 mice to a transient mild subcortical ischemia and examined cerebrovascular function at chronic timepoints as well as reactive astrocytes and A{beta} deposition post-mortem. RESULTS: Baseline cerebral blood flow and cerebrovascular reactivity (CVR) are both influenced by anesthesia regimen. A{beta} strongly impairs CVR at earlier ages, while mild ischemia impairs CVR at later ages. Mild ischemia reduces neurovascular coupling more strongly than A{beta} and synergistically increases A{beta} deposition in Tg2576 mice. DISCUSSION: Stroke-induced cerebrovascular dysfunction and astrocyte reactivity persist for long periods after the injury. Although there is variability in the spatiotemporal progression of ischemia- and A{beta}-induced vascular impairments, they generally follow the pattern of Thal staging. Surprisingly, the ischemia+A{beta} group showed the least cerebrovascular dysfunction yet an exacerbation of A{beta} deposition, suggesting that these pathologies are connected but not tightly coupled.

neuroscience↗

bioRxiv2026

A patient-derived xenograft model of FUS::TFCP2 intraosseous rhabdomyosarcoma reveals chemoresistance and differential sensitivity to ALK inhibitors

TFCP2-rearranged rhabdomyosarcoma is an exceptionally rare and highly aggressive malignancy driven by TFCP2 gene fusions and associated with a dismal clinical prognosis. Because standardized treatment regimens are lacking, developing representative preclinical models is critical for identifying effective therapies. Here, we present a case of a 29-year-old male with rapidly progressive, metastatic pelvic intraosseous rhabdomyosarcoma (iRMS) harboring a FUS::TFCP2 fusion and anaplastic lymphoma kinase (ALK) overexpression. To evaluate therapeutic vulnerabilities, we established a patient-derived xenograft (PDX) model that faithfully recapitulated the histologic, immunohistochemical, and molecular hallmarks of the primary tumor. High-throughput in vitro pharmacological screening of PDX-derived cells demonstrated notable resistance to standard cytotoxic chemotherapies and revealed a paradoxical and selective sensitivity profile across ALK inhibitors. The PDX-derived cells were susceptible to crizotinib, brigatinib, and ceritinib, yet resistant to the more selective second- and third-generation inhibitors alectinib and lorlatinib. Notably, next-generation ROS1/pan-TRK inhibitors (entrectinib, repotrectinib, and taletrectinib) demonstrated superior efficacy compared to the fourth-generation ALK inhibitor NVL-655. Our findings establish a validated preclinical PDX model for FUS::TFCP2 iRMS and suggest that multi-targeted tyrosine kinase inhibition may offer a more viable therapeutic strategy than narrow-spectrum ALK targeting or conventional chemotherapy.

cancer biology↗

bioRxiv2026

A humanized Aβ mouse model reveals E4-dependent cognitive impairments, microglial activation, and cerebrovascular dysfunction

Apolipoprotein E4 (E4) increases the risk of Alzheimers disease (AD) by up to 12-fold. However, understanding of the mechanisms underlying this increased risk has been limited by a lack of preclinical models that accurately reflect the effects of E4 in the presence of humanized non-mutant amyloid-{beta} precursor protein (hA{beta}PP). Therefore, we studied novel humanized APOE and hA{beta}PP mice to investigate the contributions of the E4 genotype to cognitive, inflammatory, and vascular dysfunction, specifically comparing male and female E3/hA{beta}PP and E4/hA{beta}PP mice. E4/hA{beta}PP mice exhibited impaired nest-building behavior and novel object recognition compared with E3/hA{beta}PP mice. Microglial content was higher in E4/hA{beta}PP mice, whereas astrocyte content was not different across groups. E4/hA{beta}PP mice had greater carotid and cerebral artery stiffness, and higher collagen I content in cerebral arteries than E3/hA{beta}PP mice. Under static pressure, cerebral artery endothelium-dependent and endothelium-independent vasodilation were similar across genotypes. However, high pulse pressure selectively impaired cerebral artery endothelial function in E4/hA{beta}PP mice, with the greatest impairment observed in females. The E4/hA{beta}PP mice also exhibited higher cortical expression of Nox2 and Sod1 and elevated cerebral artery Il1b expression. As such, E4/hA{beta}PP mice exhibit convergent cognitive, inflammatory, and vascular abnormalities that recapitulate several features of AD. Elevated pulse pressure revealed an E4-dependent vulnerability of the cerebral vasculature, suggesting that vascular stress may be an important contributor to disease risk. Together, our findings support the use of the APOExhA{beta}PP model to investigate the mechanisms by which E4 promotes vascular dysfunction, neuroinflammation, and cognitive impairment in AD.

physiology↗

bioRxiv2026

Aging macaques bridge the translational gap in perivascular space biology

The prevalence of MR-visible perivascular spaces (PVS) is age-dependent in rhesus macaques. Automated quantification in 94 male and female animals ranging 5-28 years of age demonstrated a robust association between age and PVS burden, with an anatomical distribution paralleling that of humans. Preliminary ex vivo validation confirmed that the MRI-detected tubular structures correspond to perivascular spaces. These findings establish the rhesus macaque as a tractable model for understanding the role of perivascular dysfunction in age-related brain vulnerability.

neuroscience↗

bioRxiv2025

The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologies

Apolipoprotein E (APOE) genotype is well known to influence both amyloid-{beta} (A{beta}) and tau pathologies and risk for Alzheimers disease (AD), but it also affects -synuclein (-syn) levels, Lewy pathology and risk of dementia in Parkinsons disease (PD) and dementia with Lewy bodies (DLB). The APOE-R136S (Christchurch, CC) point mutation has been shown to protect against AD pathology and dementia, however, the molecular mechanisms underlying this protection and its effects on -syn pathology are not well understood. Using CRISPR/Cas9 technology, we created a CC arginine-to-serine point mutation at the conserved location in mouse APOE (R128S) to understand its effects on A{beta}, tau and -syn pathologies. We crossed these APOE CC mice to 5xFAD, PS19 and A53T-Syn-GFP (A53T) mice. Using these various double mutant mice, we tested the effect of mouse APOE CC on different proteinopathies, including A{beta}, tau, A{beta}-induced tau after paired helical filament (PHF)-tau intracortical injections, and -syn after preformed fibril (PFF) intracortical and intramuscular injections. We used immunohistochemical, biochemical and behavioral measures to test for protective effects of APOE CC on these different proteinopathies. Heterozygous (Het) and homozygous (Hom) APOE CC mice showed increased plasma cholesterol and triglyceride levels, as seen in humans, but no differences in body or brain weight, or life expectancy. APOE CC decreased A{beta}-induced tau pathologies in PHF-tau injected 5xFAD;Hom mice but did not change A{beta}-plaque pathology in 5xFAD mice or tau pathology in PS19 mice. Although A{beta} levels, tau levels and mouse sex correlated strongly with the behavioral performance, we only detected subtle effects of APOE CC on anxiety-like behaviors in crosses with 5xFAD, PS19 and PHF-tau injected 5xFAD mice. Interestingly, Het and Hom APOE CC mice both showed reduced formation and spread of Lewy pathology in brain after intracortical -syn PFF injection and reduced formation in spinal cord after -syn PFF injection into the hindlimb gastrocnemius muscle in A53T mice. Our study emphasizes the protective effects of the APOE CC variant against different proteinopathies important for dementia and movement disorders, including A{beta} plaque, tau and -syn, and suggests that targeting APOE CC could provide new therapeutic strategies for AD, DLB and PD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/686857v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1104377org.highwire.dtl.DTLVardef@bd6c70org.highwire.dtl.DTLVardef@1a4e44org.highwire.dtl.DTLVardef@1087d7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Cerebral blood flow in elastin haploinsufficient and 3xTg-AD mice

Artery structural properties and Alzheimers disease (AD) pathology are individually associated with impaired cerebrovascular function; however, the interaction of these factors is unclear. Furthermore, while elastin haploinsufficient (Eln+/-) mice are known to have impaired cerebrovascular function, sex differences for this effect have not been previously studied. To answer these questions, we crossed middle-aged and old Eln+/-mice with 3xTg-AD mice. We measured cerebral blood flow (CBF) using arterial spin labeling MRI at rest and during hypercapnia to calculate cerebrovascular reactivity (CVR). We also assessed neuroinflammation by microglia and astrocyte cell counts. We found that Eln+/- mice had lower resting blood flow rate in the cerebral cortex compared with Eln+/+ mice, but Eln+/- mice had an intact hypercapnic response, resulting in better CVR compared with Eln+/+ in hippocampus. Sex did not impact resting blood flow or CVR. 3xTg-AD mice had a lower resting CBF than non-AD mice, and there was an interaction between Eln genotype and AD mutations on CVR, such that Eln+/-x 3xTg-AD mice had the poorest hippocampal CVR of all groups. Glia cell counts were highly dependent on brain region, with Eln+/- having more microglia but fewer astrocytes, while 3xTg-AD having higher both microglia and astrocytes. While sex also impacted glial cell counts, we found no interactions between sex and Eln genotype. Our results demonstrate that elastin haploinsufficiency and AD mutations individually result in lower resting CBF, and the combination of these leads to impaired CVR. NEW & NOTEWORTHYThe findings of this study demonstrate that elastin haploinsufficiency leads to lower resting cerebral blood flow, but also greater cerebrovascular reactivity. However, elastin haploinsufficiency interacts with Alzheimers disease mutations to impair cerebrovascular reactivity. These results suggest that multiple insults, such as changes to the extracellular matrix combined with genetic risk factors, are needed to impact cerebrovascular reactivity.

physiology↗

bioRxiv2021

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (A{beta}) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n=174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and A{beta} pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p=0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p=0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p<0.0001), but other features including ARTAG (p=0.03) and hippocampal atrophy (p=0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

pathology↗

bioRxiv2020

Genome-wide assessment of REST binding profiles reveals distinctions between human and mouse hippocampus

Background The transcriptional repressor, RE1 Silencing Transcription Factor (REST), recognized historically as a master regulator of neuronal gene expression during mouse development, has recently been ascribed roles in human aging and neurodegenerative disorders. However, REST’s role in healthy adult human brain, and how faithfully mouse models reproduce REST function in human brain, is not known.Results Here, we present the first genome-wide binding profile for REST in both mouse and human postnatal hippocampus. We find the majority of REST-bound sites in human hippocampus are unique compared to both mouse hippocampus and to all other reported human ENCODE cell types. Genes associated with unique REST-bound sites include previously unidentified categories related to innate immunity and inflammation signaling, suggesting species specific roles for REST in protecting human brain health.Conclusions Our results suggest newly evolved functions for REST in maintaining human brain health.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗