Inflammopharmacology, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 21, 2024
Language: Английский
Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)
Published: Jan. 4, 2025
Accumulation of β-amyloid (Aβ) in the brain is a hallmark Alzheimer's Disease (AD). Cerebral deposition Aβ initiates deteriorating pathways which eventually can lead to AD. However, exact mechanisms are not known. A possible pathway could be that affects cerebral vessels, causing inadequate cerebrovascular function. In present study, we examined if accumulation associated with reduced blood flow response (CBF) neuronal activation by visual stimulation (ΔCBFVis.Act.) cognitively normal subjects from Metropolit Danish Male Birth Cohort. 64 participated study. ΔCBFVis.Act. was measured using arterial spin labelling (ASL) combined blood-oxygen-level-dependent (BOLD) MRI. Neuronal obtained flickering checkerboard presented on screen MRI-scanner. Brain and glucose metabolism were assessed PET imaging radiotracers [11C]Pittsburgh Compound-B (PiB) [18F]Fluorodeoxyglucose (FDG), respectively. Cortical thickness structural correlated negatively ( $$\beta$$ = -32.1 [95% confidence interval (CI): -60.2; -4.1], r -0.30, p 0.025) PiB standardized uptake value ratio (SUVr) regions activated stimulation. did correlate FDG SUVr 1.9 [CI: -23.8; 27.6], 0.02, 0.88) or cortical 10.3 -8.4; 29.0], 0.15, 0.27) regions. Resting CBF neither -17.8 [CI:-71.9; 36.2], =- 0.09, 0.51) nor remaining cortex 5.2 [CI:-3.9; 14.2], 0.26). We found correlation between high activation, indicating link impaired The impairment thinning hypometabolism, suggesting affecting vessel function very early pathology leading neurodegenerative disease.
Language: Английский
Citations
2
Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(11), P. 101760 - 101760
Published: Oct. 8, 2024
SummaryThe blood-brain barrier (BBB) plays central roles in the maintenance and health of brain. Its mechanisms to safeguard brain against xenobiotics endogenous toxins also make BBB primary obstacle development drugs for nervous system (CNS). Here, we review classic examples intersection clinical medicine, drug delivery, BBB. We highlight role lipid solubility (heroin), saturable brain-to-blood (efflux: opiates) blood-to-brain (influx: nutrients, vitamins, minerals) transport systems, adsorptive transcytosis (viruses incretin receptor agonists). examine how disruption that occurs certain diseases (tumors) can be modulated (osmotic agents microbubbles) used deliver treatments, extracellular pathways gaining access CNS (albumin antibodies). In summary, this provides a historical perspective key delivery disease.Graphical abstract
Language: Английский
Citations
6
Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15
Published: July 18, 2023
The 5xFAD mouse is a popular model of familial Alzheimer's disease (AD) that characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the has not been comprehensively phenotyped for vascular metabolic perturbations over its lifespan.Male female wild type (WT) littermates underwent in vivo18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, 12 months age to assess regional glucose metabolism. A separate cohort mice (4, 8, months) "vessel painting" which labels all cerebral vessels were analyzed characteristics such as vessel density, junction length, network complexity, number collaterals, diameter.With increasing age, on cortical surface both WT showed increased densities. collateral between middle artery (MCA) anterior posterior arteries decreased with but diameters significantly only mice. MCA total length density compared 4 months. Analysis 18F-FDG uptake revealed significant differences spanning 4-12 Broadly, males had In most regions, reduced across their lifespan.While exhibits AD-like deficits are associated Aβ deposition, we found features males, females. Interestingly, male exhibited opposite effects uptake. supplies blood large portions somatosensory cortex motor visual alongside collaterals coincided higher rates Thus, potential mismatch demand delivery nutrients face could contribute progressive seen model.
Language: Английский
Citations
15
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
Citations
5
Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown
Published: July 24, 2024
Language: Английский
Citations
4
International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2433 - 2433
Published: March 8, 2025
Alzheimer’s disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis AD. However, current studies have recognized a prominent role cerebrovascular dysfunction in We recently reported that SNPs soluble epoxide hydrolase (sEH) linked AD human genetic long-term administration sEH inhibitor attenuated cerebral vascular cognitive rat model mechanisms linking changes function neuroprotective actions inhibitors remain be determined. This study investigated effects inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood–brain barrier (BBB) function, neuroinflammation, hAPP/PS1 TgF344-AD observed predominant β-amyloid brains 9–10-month-old rats TPPU treatment for three months reduced burden. functional hyperemic response whisker stimulation was rats, normalized response. TPPU, mitigated capillary rarefaction, BBB leakage, activation astrocytes microglia rats. increased expression pre- post-synaptic proteins loss hippocampal neurons impairments which confirmed transcriptome GO analysis. These results suggest could novel therapeutic strategy
Language: Английский
Citations
0
Published: Jan. 1, 2025
Language: Английский
Citations
0
Journal of Neuroscience Research, Journal Year: 2023, Volume and Issue: 101(12), P. 1840 - 1848
Published: Sept. 19, 2023
Abstract Pericytes are critical yet understudied cells that a central component of the neurovascular unit. They connected to cerebrovascular endothelium and help control vascular contractility maintain blood–brain barrier. Pericyte dysfunction has potential mediate many deleterious consequences ischemic stroke. Current therapeutics designed be administered after stroke onset limit damage, but there few options target risk factors pre‐ischemia which likely contribute outcomes. Here, we focus on role pericytes in health disease, discuss how pericyte can increase injury. Additionally, note despite importance relatively current therapeutic function.
Language: Английский
Citations
7
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
Citations
2
International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14092 - 14092
Published: Sept. 14, 2023
Cerebral amyloid angiopathy (CAA) is characterized by β (Aβ) accumulation in the blood vessels and associated with cognitive impairment Alzheimer's disease (AD). The increased of Aβ also present retinal a significant correlation between brain deposition was demonstrated living patients animal AD models. can be result impaired transcytosis and/or dysfunctional ocular glymphatic system during aging. We analyzed changes mRNA protein expression major facilitator superfamily domain-containing protein2a (Mfsd2a), regulator transcytosis, Aquaporin4 (Aqp4), key player implicated functioning system, retinas 4- 12-month-old WT 5xFAD female mice. A strong decrease Mfsd2a observed 4 M 12 retinas. increase srebp1-c could at least partially responsible for pericyte (CD13+) coverage suggests that loss downregulation these experimental groups. Aqp4 accompanied decreased perivascular indicative system. findings this study reveal mislocalization physiological (WT) pathological (5xFAD) aging, indicating their importance as putative targets development new treatments improve regulation or function
Language: Английский
Citations
4