Hypertension, Neurodegeneration, and Cognitive Decline DOI Creative Commons
Anthony G. Pacholko, Costantino Iadecola

Hypertension, Journal Year: 2024, Volume and Issue: 81(5), P. 991 - 1007

Published: March 1, 2024

Elevated blood pressure is a well-established risk factor for age-related cognitive decline. Long linked to impairment on vascular bases, increasing evidence suggests potential association of hypertension with the neurodegenerative pathology underlying Alzheimer disease. Hypertension well known disrupt structural and functional integrity cerebral vasculature. However, mechanisms by which these alterations lead brain damage, enhance pathology, promote remain be established. Furthermore, critical questions concerning whether lowering antihypertensive medications prevents have not been answered. Recent developments in neurovascular biology, imaging, epidemiology, as new clinical trials, provided insights into issues. In particular, basic findings link between dysfunction pathobiology neurodegeneration shed light overlap pathology. this review, we will examine progress made relationship and, after evaluation evidence, attempt identify remaining knowledge gaps future research directions that may advance our understanding one leading health challenges time.

Language: Английский

Magnetic ResonanceImages Implicate That Glymphatic Alterations Mediate Cognitive Dysfunction inAlzheimer Disease DOI Creative Commons

Jung‐Lung Hsu,

Yi‐Chia Wei, Cheng‐Hong Toh

et al.

Annals of Neurology, Journal Year: 2022, Volume and Issue: 93(1), P. 164 - 174

Published: Oct. 10, 2022

Objective The glymphatic system cleans amyloid and tau proteins from the brain in animal studies of Alzheimer disease (AD). However, there is no direct evidence showing this humans. Methods Participants (n = 50, 62.6 ± 5.4 years old, 36 women) with AD normal controls underwent positron emission tomography (PET), PET, structural T1‐weighted magnetic resonance imaging, neuropsychological evaluation. Whole‐brain activity was measured by diffusion tensor image analysis along perivascular space (DTI‐ALPS). Results ALPS‐indexes showed negative correlations deposition on PET images positive cognitive scores even after adjusting for age, sex, education, APOE4 genotype covariates multiple AD‐related regions (all p < 0.05). Mediation that ALPS‐index acted as a significant mediator between regional standardized uptake value ratios dysfunction correcting regions. These are responsible attention, memory, executive function, which vulnerable to sleep deprivation. Interpretation Glymphatic may act gray matter volumes. provide useful progression or treatment biomarkers patients an indicator modulation activity. ANN NEUROL 2023;93:164–174

Language: Английский

Citations

118
Multisensory gamma stimulation promotes glymphatic clearance of amyloid DOI Creative Commons
Mitchell H. Murdock,

Cheng-Yi Yang,

Na Sun

et al.

Nature, Journal Year: 2024, Volume and Issue: 627(8002), P. 149 - 156

Published: Feb. 28, 2024

Abstract The glymphatic movement of fluid through the brain removes metabolic waste 1–4 . Noninvasive 40 Hz stimulation promotes neural activity in multiple regions and attenuates pathology mouse models Alzheimer’s disease 5–8 Here we show that multisensory gamma influx cerebrospinal efflux interstitial cortex 5XFAD model disease. Influx was associated with increased aquaporin-4 polarization along astrocytic endfeet dilated meningeal lymphatic vessels. Inhibiting clearance abolished removal amyloid by stimulation. Using chemogenetic manipulation a genetically encoded sensor for neuropeptide signalling, found vasoactive intestinal peptide interneurons facilitate regulating arterial pulsatility. Our findings establish novel mechanisms recruit system to remove amyloid.

Language: Английский

Citations

99
Astrocyte Endfeet in Brain Function and Pathology: Open Questions DOI
Blanca Díaz‐Castro, Stefanie Robel, Anusha Mishra

et al.

Annual Review of Neuroscience, Journal Year: 2023, Volume and Issue: 46(1), P. 101 - 121

Published: Feb. 28, 2023

Astrocyte endfeet enwrap the entire vascular tree within central nervous system, where they perform important functions in regulating blood-brain barrier (BBB), cerebral blood flow, nutrient uptake, and waste clearance. Accordingly, astrocyte contain specialized organelles proteins, including local protein translation machinery highly organized scaffold which anchor channels, transporters, receptors, enzymes critical for astrocyte-vascular interactions. Many neurological diseases are characterized by loss of polarization specific endfoot dysregulation, BBB disruption, altered clearance, or, extreme cases, coverage. A role has been demonstrated or postulated many these conditions. This review provides an overview development, composition, function, pathological changes highlights gaps our knowledge that future research should address.

Language: Английский

Citations

93
Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis DOI Open Access
Raquel Sánchez‐Varo, Marina Mejias‐Ortega, Juan José Fernandez-Valenzuela

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(10), P. 5404 - 5404

Published: May 12, 2022

Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to discovery heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due repeated failure translational applications from animal models human patients, along with recent advances genetic susceptibility our current understanding on biology, these have evolved over time an attempt better reproduce complexity this devastating improve their applicability. In review, we provide a comprehensive overview about major pathological elements AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation glial dysfunction), discussing knowledge that available mouse provided mechanisms underlying disease. Moreover, highlight pros cons models, revolution offered by concomitant use omics technologies may lead more rapid improvement present battery.

Language: Английский

Citations

82
The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis DOI Creative Commons

Francesca R. Buccellato,

Marianna D’Anca, María Serpente

et al.

Biomedicines, Journal Year: 2022, Volume and Issue: 10(9), P. 2261 - 2261

Published: Sept. 13, 2022

Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson's (PD) a movement disorder. These two disorders share accumulation toxic proteins as pathological hallmark. The lack definitive disease-modifying treatments for these neurogenerative diseases has led to hypothesis new pathogenic mechanisms target and design potential therapeutic approaches. recent observation that glymphatic system supposed be responsible cerebrospinal fluid into brain clearance metabolic waste study its involvement in pathogenesis classic proteinopathies. Aquaporin-4 (AQP4), water channel located endfeet astrocyte membrane, considered primary driver system, defective AQP4-mediated drainage been linked objective present review body knowledge links AD PD other lifestyle factors such sleep deprivation exercise may influence function. We will also focus on neuroimaging approaches could identify marker detect changes.

Language: Английский

Citations

80
Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation DOI Creative Commons
Ryszard S. Gomolka, Lauren M. Hablitz, Humberto Mestre

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Feb. 9, 2023

The glymphatic system is a fluid transport network of cerebrospinal (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial (ISF), ultimately establishing directional clearance solutes. CSF facilitated by expression aquaporin-4 (AQP4) water channels on endfeet astrocytes. Mice genetic deletion AQP4 (AQP4 KO) exhibit abnormalities in structure and molecular transport. Yet, no studies have systematically examined how these correlate function. Here, we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) intravoxel-incoherent motion (IVIM) DWI, while evaluating function using standard dynamic contrast-enhanced to better understand disrupted after AQP4. KO mice had larger spaces total volumes resulting higher content reduced space volumes, despite similar production rates vascular density compared wildtype mice. volume likely resulted increased slow but not fast diffusion measures coincided influx. This markedly altered may result from reduction clearance, leading enlargement stagnation space. Overall, useful tool evaluate serve as valuable translational biomarker study glymphatics human disease.

Language: Английский

Citations

80
Glymphatic system impairment in Alzheimer’s disease: associations with perivascular space volume and cognitive function DOI
Xue Zhang, Yue Wang,

Bingjie Jiao

et al.

European Radiology, Journal Year: 2023, Volume and Issue: 34(2), P. 1314 - 1323

Published: Aug. 23, 2023

Language: Английский

Citations

61
Interaction Between the Glymphatic System and α-Synuclein in Parkinson’s Disease DOI
Yu Zhang, Cui Zhang,

Xu-Zhong He

et al.

Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 60(4), P. 2209 - 2222

Published: Jan. 13, 2023

Language: Английский

Citations

60
Activation of aryl hydrocarbon receptor (AhR) in Alzheimer’s disease: role of tryptophan metabolites generated by gut host-microbiota DOI Creative Commons
Antero Salminen

Journal of Molecular Medicine, Journal Year: 2023, Volume and Issue: 101(3), P. 201 - 222

Published: Feb. 9, 2023

Abstract Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked disorders, such as neuropsychiatric conditions Alzheimer’s disease (AD). l -tryptophan metabolites short-chained fatty acids (SCFA) are major messengers the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) main targets of tryptophan microvessels which possess an enriched expression AhR protein. The Ah receptor is evolutionarily conserved, ligand-activated transcription factor not only a sensor xenobiotic toxins but also pleiotropic regulator both developmental processes age-related tissue degeneration. Major microbiota-produced involve indole derivatives, e.g., 3-pyruvic acid, 3-acetaldehyde, indoxyl sulfate, whereas indoleamine 2,3-dioxygenases (IDO/TDO) intestine cells activate kynurenine (KYN) pathway generating KYN metabolites, activators signaling. Chronic kidney (CKD) increases serum level sulfate promotes AD pathogenesis, it disrupts integrity blood–brain barrier (BBB) impairs cognitive functions. Activation signaling disturbs vascular homeostasis brain; (i) controls blood flow via renin-angiotensin system, (ii) inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production vasodilatation, (iii) induces oxidative stress, stimulates inflammation, cellular senescence, enhances calcification walls. All these alterations evident cerebral amyloid angiopathy (CAA) pathology. Moreover, can disturb circadian regulation probably affect glymphatic flow. It seems plausible that gut BBB activation aggravates Key messages Dysbiosis associated dementia disease. Tryptophan from host-microbiota to brain. aryl protein blood-brain barrier. inflammation pathology

Language: Английский

Citations

56
Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson’s disease DOI Creative Commons
Xiaoli Si,

Shaobing Dai,

Yi Fang

et al.

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 56, P. 125 - 136

Published: March 20, 2023

The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays pathogenic role in Parkinson's disease (PD); however, molecular mechanism PD remains elusive. To explore whether matrix metalloproteinase-9 (MMP-9)-mediated β-dystroglycan (β-DG) cleavage is involved regulation aquaporin-4 (AQP4) polarity-mediated PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced A53T mice were used this study. function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, administered investigate GM6001, MMP-9 MMP-9/β-DG regulating AQP4. expression distribution AQP4, MMP-9, β-DG assessed western blotting, immunofluorescence, co-immunoprecipitation. ultrastructure basement membrane (BM)-astrocyte endfeet detected transmission electron microscopy. Rotarod open-field tests performed evaluate motor behavior. Perivascular influx efflux cerebral spinal fluid tracers reduced MPTP-induced with impaired polarization. inhibition aggravated reactive astrogliosis, drainage restriction, dopaminergic neuronal loss mice. cleaved upregulated both mice, polarized localization astrocyte endfeet. restored BM-astrocyte endfeet-AQP4 integrity attenuated metabolic perturbations loss. depolarization contributes aggravates pathologies, MMP-9-mediated regulates through polarization PD, which may provide novel insights into pathogenesis

Language: Английский

Citations

49