Cerebrovascular Dysfunction in Alzheimer’s Disease and Transgenic Rodent Models

Journal of Experimental Neurology, Journal Year: 2024, Volume and Issue: 5(2), P. 42 - 64

Published: Jan. 1, 2024

Alzheimer’s Disease (AD) and Disease-Related Dementia (ADRD) are the primary causes of dementia that has a devastating effect on quality life is tremendous economic burden healthcare system. The accumulation extracellular beta-amyloid (Aβ) plaques intracellular hyperphosphorylated tau-containing neurofibrillary tangles (NFTs) in brain hallmarks AD. They also thought to be underlying cause inflammation, neurodegeneration, atrophy, cognitive impairments accompany discovery APP, PS1, PS2 mutations increase Aβ production families with early onset familial AD led development numerous transgenic rodent models These have provided new insight into role AD; however, they do not fully replicate pathology patients. Familial patients elevate represent only small fraction In contrast, those late-onset sporadic constitute majority cases. This observation, along failure previous clinical trials targeting or Tau modest success recent using monoclonal antibodies, reappraisal view sole factor pathogenesis More studies established cerebral vascular dysfunction one earliest changes seen AD, 67% candidate genes linked expressed vasculature. Thus, there an increasing appreciation contribution National Institute Aging (NIA) Foundation recently prioritized it as focused research area. review summarizes strengths limitations most commonly used animal current views about versus cerebrovascular

Language: Английский

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Traumatic brain injury alters the effects of class II invariant peptide (CLIP) antagonism on chronic meningeal CLIP + B cells, neuropathology, and neurobehavioral impairment in 5xFAD mice

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: June 27, 2024

Abstract Background Traumatic brain injury (TBI) is a significant risk factor for Alzheimer’s disease (AD), and accumulating evidence supports role adaptive immune B T cells in both TBI AD pathogenesis. We previously identified cell major histocompatibility complex class II (MHCII)-associated invariant chain peptide (CLIP)-positive expansion after TBI. also showed that antagonizing CLIP binding to the antigen presenting groove of MHCII acutely reduced + splenic was neuroprotective. The current study investigated chronic effects 5xFAD mouse model, with without Methods 12-week-old male wild type (WT) mice were administered either antagonist (CAP) or vehicle, once at 30 min sham lateral fluid percussion (FPI). Analyses included flow cytometric analysis dural meninges spleen, histopathological brain, magnetic resonance diffusion tensor imaging, cerebrovascular analysis, assessment motor neurobehavioral function over ensuing 6 months. Results 9-month-old had significantly more compared age-matched WT mice. A one-time treatment CAP this population Importantly, improved some immune, histopathological, impairments six Although FPI did not further elevate meningeal cells, it negate ability reduce 3 months age exacerbated aspects pathology mice, including reducing hippocampal neurogenesis, increasing plaque deposition CA3, altering microgliosis, disrupting structure. ameliorated but all these effects.

Language: Английский

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Vascular amyloidβ load in the meningeal arterial network correlates with loss of cerebral blood flow and pial collateral vessel enlargement in the J20 murine model of Alzheimer's disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Global reduction in cerebral blood flow (CBF) is an early pathology Alzheimer's disease, preceding significant plaque accumulation and neurological decline. Chronic reduced CBF subsequent tissue oxygenation glucose may drive neurodegeneration, yet the underlying cause of globally remains unclear. Using premortem delivery Methoxy-XO4 to label Aβ, arterial vascular labeling, we assessed Aβ burden on pial artery/arteriole network aged male female WT J20 AD mice. The selectively displayed extensive burden. Pial collateral arteriole vessels, by-pass system that reroutes during occlusion, enlargement Despite this, was decreased by approximately 15% 12-month mice when compared littermates. Significant meningeal contribute restriction CBF. Redistribution through enlarged vessels serve as a compensatory mechanism alter disease progression cases CAA.

Language: Английский

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Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17377 - 17377

Published: Dec. 12, 2023

Research into Alzheimer's Disease (AD) describes a link between AD and the resident immune cells of brain, microglia. Further, this suspected is thought to have underlying sex effects, although mechanisms these effects are only just beginning be understood. Many insights result policies put in place by funding agencies such as National Institutes Health (NIH) consider biological variable (SABV) move towards precision medicine due continued lackluster therapeutic options. The purpose review provide an updated assessment current research that summarizes differences pertaining microglia their varied responses AD.

Language: Английский

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Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice

Fluids and Barriers of the CNS, Journal Year: 2024, Volume and Issue: 21(1)

Published: March 27, 2024

Abstract Background Patients with Alzheimer's disease (AD) develop blood–brain barrier dysfunction to varying degrees. How aging impacts Aβ pathology, function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice investigate changes levels, over time. Methods wild-type (WT) were aged between 9.5 15.5 months tested for spatial learning reference memory the Morris Water Maze (MWM). After behavior testing, implanted acute cranial windows intravenously injected fluorescent-labeled dextrans assess their vivo distribution brain by two-photon microscopy. Images processed segmented obtain intravascular intensity, extravascular vessel diameters as a measure of integrity. Mice sacrificed after imaging isolate plasma measuring levels. The effect age genotype evaluated each assay using generalized or cumulative-linked logistic mixed-level modeling model selection Akaike Information Criterion (AICc). Pairwise comparisons identify outcome differences two groups. Results displayed deficits compared age-matched WT MWM assay, which worsened age. Memory impairment was evident 2–threefold higher escape latencies, twofold greater cumulative distances until they reach platform, twice frequent use repetitive search strategies pool when mice. Presence rd1 allele performance at all ages but did not alter rate probe trial outcomes. 9.5-month-old 15.5-month-old had 40 42 levels ( p < 0.001) 2.5-fold = 0.007) Image analysis showed that intra- dextran intensities significantly different 9.5- Conclusion continue increased while aging. Given MP limitations, further investigation smaller molecular weight markers combined advanced techniques would be needed reliably subtle integrity

Language: Английский

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Super-resolution ultrasound imaging reveals temporal cerebrovascular changes with disease progression in female 5×FAD mouse model of Alzheimer's disease: correlation with pathological impairments

EBioMedicine, Journal Year: 2024, Volume and Issue: 108, P. 105355 - 105355

Published: Sept. 17, 2024

Language: Английский

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In vivo reactive astrocyte imaging using [18F]SMBT-1 in tauopathy and familial Alzheimer’s disease mouse models - a multitracer study

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 23, 2023

Background: Reactive astrocytes play important roles in the development of Alzheimer’s disease (AD) and primary tauopathies. Here, we aim to investigate relationship between reactive astrocytes, tau amyloid beta, microgliosis glucose metabolism by using multitracer imaging widely used tauopathy familial AD mouse models. Results: Positron emission tomography (PET) [¹⁸F]SMBT-1 (monoamine oxidase-B), [¹⁸F]florbetapir (amyloid-beta), [¹⁸F]PM-PBB3 (tau), [¹⁸F]DPA-714 (translocator protein) [¹⁸F]fluorodeoxyglucose (FDG) was carried out 3- 7-month-old rTg4510 mice, 5×FAD mice aged-matched wild-type mice. We found increased regional [¹⁸F]SMBT-1, uptake, hypoglucose brains with accumulation as well higher amyloid-beta compared age-matched Conclusion: In summary, these findings provide in-vivo evidence for microglial activation, cerebral animal models AD.

Language: Английский

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Levetiracetam modulates brain metabolic networks and transcriptomic signatures in the 5XFAD mouse model of Alzheimer’s disease

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Jan. 24, 2024

Introduction Subcritical epileptiform activity is associated with impaired cognitive function and commonly seen in patients Alzheimer’s disease (AD). The anti-convulsant, levetiracetam (LEV), currently being evaluated clinical trials for its ability to reduce improve AD. purpose of the current study was apply pharmacokinetics (PK), network analysis medical imaging, gene transcriptomics, PK/PD modeling a cohort amyloidogenic mice establish how LEV restores or drives alterations brain networks dose-dependent basis using rigorous preclinical pipeline MODEL-AD Preclinical Testing Core. Methods Chronic administered 5XFAD both sexes 3 months based on allometrically scaled dose levels from PK models. Data collection consisted multi-modal approach utilizing 18 F-FDG PET/MRI imaging analysis, transcriptomic analyses, modeling. Results Pharmacokinetics showed sex dependence C max , CL/F, AUC 0-∞ simulations used estimate regimens. dosing at 10, 30, 56 mg/kg, specific regional differences uptake, whole covariance measures such as clustering coefficient, degree, density, connection strength (i.e., positive negative). In addition, via nanoString changes expression pathways consistent uptake changes, concentration key genes, but not Discussion This represents first report detailing relationships metabolic resulting administration mice. Overall, our results highlight non-linear kinetics sex, where demonstrated dose- concentration-dependent along cerebral metabolism, and/or homeostatic mechanisms relevant human AD, which aligned closely images. Collectively, this show cases value multimodal connectomic, transcriptomic, pharmacokinetic further investigate dependent studies, translational toward informing design.

Language: Английский

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Lifespan Super-Resolution Ultrasound Imaging Reveals Temporal Evolution of Cerebrovascular Alterations in the 5×FAD Mouse Model of Alzheimer's Disease: Correlation with Pathological Impairments

Published: Jan. 1, 2024

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Language: Английский

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In vivo reactive astrocyte imaging using [18F]SMBT-1 in tauopathy and familial Alzheimer's disease mouse models: A multi-tracer study

Journal of the Neurological Sciences, Journal Year: 2024, Volume and Issue: 462, P. 123079 - 123079

Published: June 5, 2024

Language: Английский

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