New perspectives on the glymphatic system and the relationship between glymphatic system and neurodegenerative diseases

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: 205, P. 106791 - 106791

Published: Jan. 6, 2025

Neurodegenerative diseases (ND) are characterized by the accumulation of aggregated proteins. The glymphatic system, through its rapid exchange mechanisms between cerebrospinal fluid (CSF) and interstitial (ISF), facilitates movement metabolic substances within brain, serving functions akin to those peripheral lymphatic system. This emerging waste clearance mechanism offers a novel perspective on removal pathological in ND. article elucidates recent discoveries regarding system updates relevant concepts model. It discusses potential roles ND, including Alzheimer's disease (AD), Parkinson's (PD), multiple atrophy (MSA), proposes as therapeutic target for these conditions.

Language: Английский

---

The aging human brain exhibits reduced cerebrospinal fluid flow during sleep due to both neural and vascular factors

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

Published: Feb. 24, 2025

Aging reduces the quality and quantity of sleep, greater sleep loss over lifespan is predictive neurodegeneration cognitive decline. One mechanism by which could contribute to impaired brain health through disruption cerebrospinal fluid (CSF) circulation. CSF primary waste transport system brain, in young adults, waves are largest during NREM sleep. However, whether sleep-dependent physiology changes aging not known, due technical challenges performing neuroimaging studies We collected simultaneous fast fMRI EEG data measure large-scale flow healthy older adults tested there were age-related dynamics nighttime found that was reduced this reduction linked frontal delta power global hemodynamic oscillations To identify mechanisms underlying flow, we used sensory vasoactive stimuli drive daytime task experiments, both neural cerebrovascular physiological contributed Finally, associated with gray matter atrophy aging. Together, these results demonstrate human has identifies neurovascular decline, suggesting targets for future interventions.

Language: Английский

---

Linkage of circadian rhythm disruptions with Alzheimer’s disease and therapeutic interventions

Acta Pharmaceutica Sinica B, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

---

Choroid plexus free‐water correlates with glymphatic function in Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(5)

Published: May 1, 2025

Abstract INTRODUCTION Free‐water imaging of the choroid plexus (CP) may improve evaluation Alzheimer's disease (AD). METHODS Our study investigated role free‐water fraction (FWf) CP in AD among 216 participants (133 Aβ+ and 83 Aβ– controls) enrolled NeuroBank‐Dementia cohort at Ruijin Hospital (RJNB‐D). The Disease Neuroimaging Initiative dataset was used for external validation. RESULTS At baseline, showed higher FWf, increased white matter hyperintensity (WMH) volume, decreased diffusion tensor image analysis along perivascular space (DTI‐ALPS). In participants, DTI‐ALPS mediated association between FWf periventricular WMH. associated with cortical tau accumulation, synaptic loss, hippocampal atrophy, cognitive performance. During follow‐up, faster than controls. DISCUSSION Elevated indicated impaired glymphatic function neurodegeneration, can be a sensitive biomarker progression. registered on ClinicalTrials.gov (NCT05623124). Highlights This found amyloid beta (Aβ)+ participants. related to function, brain burden, cognition. growth controls during follow‐up. rate exceeded that lesion accumulation serve as marker

Language: Английский

---

A “glympse” into neurodegeneration: Diffusion MRI and cerebrospinal fluid aquaporin‐4 for the assessment of glymphatic system in Alzheimer's disease and other dementias

Human Brain Mapping, Journal Year: 2024, Volume and Issue: 45(12)

Published: Aug. 15, 2024

Abstract The glymphatic system (GS) is a whole‐brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on humans limited by absence easily accessible biomarkers. Recently, promising non‐invasive methods based magnetic resonance imaging (MRI) along with aquaporin‐4 (AQP4) quantification cerebrospinal fluid (CSF) were introduced for an indirect assessment each compartments. We recruited 111 consecutive subjects presenting symptoms suggestive degenerative cognitive decline, who underwent 3 T MRI scanning including multi‐shell diffusion‐weighted images. Forty nine out also CSF examination CSF‐AQP4. CSF‐AQP4 levels measures—including (PVS) counts volume fraction (PVSVF), white matter free water (FW‐WM) mean kurtosis (MK‐WM), diffusion tensor analysis (DTI‐ALPS) (mean, left right)—were compared among patients AD ( n = 47) other diseases (nAD 24), stable mild impairment (MCI 17) cognitively unimpaired (CU 23) elderly people. Two runs conducted, first all patients; second after dividing both nAD into two subgroups gray atrophy as proxy stage. Age, sex, years education, time included confounding factors analyses. Considering whole cohort, showed significantly higher (exp(b) 2.05, p .005) FW‐WM 1.06, .043) than CU. AQP4 respect to CU 2.98, < .001). less atrophic 2.20, .006; exp(b) 1.08, .019, respectively) 2.66, .002; 1.10, subjects. Higher total 1.59, .013) centrum semiovale PVS 1.89, .016), 1.50, .036) WM PVSVF together lower MK‐WM 0.94, .006), ALPS 0.91, .043; 0.88, .010 observed more In addition, exhibited 3.39, .002) Our results indicate significant changes putative biomarkers dementias, suggesting close interaction between neurodegeneration, case AD. However, usefulness some these standalone indices activity may be hindered their dependence stage structural damage.

Language: Английский

---

Accumulation of Cerebrospinal Fluid, Ventricular Enlargement, and Cerebral Folate Metabolic Errors Unify a Diverse Group of Neuropsychiatric Conditions Affecting Adult Neocortical Functions

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 10205 - 10205

Published: Sept. 23, 2024

Cerebrospinal fluid (CSF) is a critical to brain development, function, and health. It actively secreted by the choroid plexus, it emanates from tissue due osmolar exchange constant contribution of metabolism astroglial output interstitial into ventricles brain. CSF acts as growth medium for developing cerebral cortex source nutrients signalling throughout life. Together with perivascular glymphatic movement through CSF, also remove toxins maintain metabolic balance. In this study, we focused on folate status, measuring concentrations receptor alpha (FOLR1); aldehyde dehydrogenase 1L1, known 10-formyl tetrahydrofolate (ALDH1L1 FDH); total folate. These demonstrate transport blood across blood–CSF barrier (FOLR1 + folate), primary FDH pathway ve astrocytes. Based our hypothesis that flow, drainage issues, or osmotic forces, resulting in accumulation, would have an associated imbalance, investigated status neurological conditions severity association enlarged ventricles. We found all examined had but these imbalances were not same. Given essential key cellular processes, including DNA/RNA synthesis, methylation, nitric oxide, neurotransmitter conclude ageing some form trauma life can lead accumulation ventricular enlargement result specific imbalance/deficiency condition. believe addressing imbalance may therefore alleviate many underlying deficits symptoms conditions.

Language: Английский

---

Chronic Neuronal Hyperexcitation Exacerbates Tau Propagation in a Mouse Model of Tauopathy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9004 - 9004

Published: Aug. 19, 2024

The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer's disease (AD) and other tauopathies. Recently, hypothesis has emerged suggesting that propagation linked to neuronal connections, specifically driven by hyperactivity. However, experimental validation this remains limited. In study, we investigated how from the entorhinal cortex hippocampus, circuit most susceptible pathology AD, affected selective stimulation activity along circuit. Using mouse model seed-induced combined optogenetics, found chronic connection over 4-week period resulted significant increase insoluble accumulation both hippocampus. Importantly, ratio hippocampus relative cortex, serving as an indicator transcellular spreading, was significantly higher mice subjected stimulation. These results support notion abnormal promotes propagation, thereby implicating it progression tauopathy.

Language: Английский

---

Choroid Plexus Free-Water Correlates with Glymphatic function in Alzheimer Disease: The RJNB-D Study

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

The free water imaging of choroid plexus (CP) may improve the evaluation Alzheimer's disease (AD). Our study investigated role fraction (FWf) CP in AD by including 216 participants (133 Aβ + and 83 Aβ- controls) continuously enrolled NeuroBank-Dementia cohort at Ruijin Hospital (RJNB-D). At baseline, showed higher (FWf), increased white matter hyperintensity (WMH) volume, decreased diffusion tensor image analysis perivascular space (DTI-ALPS). In participants, DTI-ALPS mediated association between FWf periventricular WMH. was associated with cortical Tau accumulation, synaptic loss, hippocampal atrophy, cognitive performance. During follow-up, faster than controls. findings suggest that elevated indicate impaired glymphatic function neurodegeneration, potentially serving as a valuable biomarker for progression.

Language: Английский

---

Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

The appearance of misfolded and aggregated proteins is a pathological hallmark numerous neurodegenerative diseases including Alzheimer's disease Parkinson's disease. Sleep disruption proposed to contribute these processes common early feature among disorders. Synucleinopathies are subclass conditions defined by the presence α-synuclein aggregates, which may not only enhance cell death, but also progression seeding formation additional aggregates in neighboring cells. mechanisms driving intercellular transmission remains unclear. We propose that sleep-active glymphatic function, caused loss precise perivascular AQP4 localization, inhibits clearance facilitates propagation seeding. examined human post-mortem frontal cortex found neocortical pathology was associated with mis-localization throughout gray matter. Using transgenic mouse model lacking adapter protein α-syntrophin, we observed localization impairs from intersititial cerebrospinal fluid. propogation, using pre-formed fibril injection, increased aggregates. Our results indicate mediated function synucleinopathy development Lewy body such as Body Dementia

Language: Английский

---

Influence of the Glymphatic System on α-Synuclein Propagation: Role of Aquaporin-4 and the Dystrophin-Associated Protein Complex

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 14, 2024

Abstract Propagation and aggregation of prion proteins, such as tau α-synuclein (αSyn), are key pathological features neurodegenerative diseases. Extracellular clearance pathways, the glymphatic system, may play a crucial role in removal these toxic proteins from brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated Parkinson’s disease, however precise mechanisms underlying pathogenic effect remain unclear. This includes how impaired function influences αSyn propagation dynamics, propagating itself function. In study, we used mouse model elucidate impact function, by measuring CSF-ISF exchange assessing AQP4 associated endfoot complex brain over time across different regions. Our results show that direct injection pre-formed fibrils leads reduced complex, but endogenous induces an enhancement suggesting compensatory upregulation response increasing load. To determine influence then employed pharmacological approach inhibit model. Acute inhibition significantly CSF clearance, chronic treatment exacerbated pathology, neurodegeneration, motor behavioural deficits mice. Together our findings modulated suggest dysregulation contribute impairment with Summary for non-scientific community The clears waste sleep. Lopes et al. α-synuclein, protein linked Parkinson’s, is cleared system. Using they channels impair contributing buildup patients’ brains.

Language: Английский

---