APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading DOI Creative Commons
Chanung Wang, Aishwarya Nambiar, Michael R. Strickland

и другие.

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(14)

Опубликована: Июнь 6, 2023

Alzheimer's disease (AD) is the most common cause of dementia. The APOE-ε4 allele apolipoprotein E (APOE) gene strongest genetic risk factor for late-onset AD. APOE genotype modulates effect sleep disruption on AD risk, suggesting a possible link between apoE and in pathogenesis, which relatively unexplored. We hypothesized that modifies Aβ deposition plaque-associated tau seeding spreading form neuritic plaque-tau (NP-tau) pathology response to chronic deprivation (SD) an isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with without AD-tau injection. found SD significantly increased peri-plaque NP-tau presence APOE4 but not APOE3. decreased microglial clustering around plaques aquaporin-4 (AQP4) polarization blood vessels also sleep-deprived APPPS1:E4 injected had altered behaviors compared APPPS1:E3 mice. These findings suggest critical modifier development SD.

Язык: Английский

ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes DOI Creative Commons
Hyein Lee, Sukhee Cho, Mi-Jin Kim

и другие.

Cell Reports, Год журнала: 2023, Номер 42(10), С. 113183 - 113183

Опубликована: Сен. 29, 2023

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, variant ε4 APOE gene (APOE4) confers greatest risk. Dysregulated glucose metabolism is an early pathological feature AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that increases glycolytic activity but impairs mitochondrial respiration astrocytes. Ultrastructural autophagy flux analyses show ApoE4-induced cholesterol accumulation lysosome-dependent removal damaged mitochondria. Acute treatment cholesterol-depleting agents restores autophagic activity, dynamics, proteomes, extended rescues Taken together, our study provides a direct link between lysosomal abnormal oxidative phosphorylation.

Язык: Английский

Процитировано

28
Cellular senescence in brain aging and cognitive decline DOI Creative Commons
Areez Shafqat, Saifullah Khan, Mohamed H. Omer

и другие.

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Ноя. 23, 2023

Cellular senescence is a biological aging hallmark that plays key role in the development of neurodegenerative diseases. Clinical trials are currently underway to evaluate effectiveness senotherapies for these However, impact on brain and cognitive decline absence neurodegeneration remains uncertain. Moreover, patient populations like cancer survivors, traumatic injury obese individuals, obstructive sleep apnea patients, chronic kidney disease patients can suffer age-related changes prematurely, suggesting they may accelerated brain. Understanding neurocognitive deficits linked conditions crucial, especially considering rapidly evolving field senotherapeutics. Such treatments could help alleviate early significantly reducing morbidity healthcare costs. This review provides translational perspective how cellular decline. We also discuss important caveats surrounding mainstream senolytics senomorphics, present emerging evidence hyperbaric oxygen therapy immune-directed therapies as viable modalities senescent cell burden.

Язык: Английский

Процитировано

28
Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders DOI Creative Commons

Xiaojie Zhao,

Siwei Zhang, Alan R. Sanders

и другие.

Complex Psychiatry, Год журнала: 2023, Номер 9(1-4), С. 154 - 171

Опубликована: Янв. 1, 2023

<b><i>Background:</i></b> Lipids are essential components of the structure and for function brain cells. The intricate balance lipids, including phospholipids, glycolipids, cholesterol, cholesterol ester, triglycerides, is crucial maintaining normal function. roles lipids lipid droplets their relevance to neurodegenerative neuropsychiatric disorders (NPDs) remain largely unknown. <b><i>Summary:</i></b> Here, we reviewed basic role as well a specific organelle, droplets, in function, highlighting potential impact altered metabolism pathogenesis Alzheimer’s disease (AD) NDPs. <b><i>Key Messages:</i></b> Brain dysregulation plays pivotal progression NPDs AD schizophrenia. Understanding cell type-specific mechanisms these diseases identifying better diagnostic biomarkers developing therapeutic strategies aiming at restoring homeostasis.

Язык: Английский

Процитировано

26
Detecting Early Cognitive Decline in Alzheimer’s Disease with Brain Synaptic Structural and Functional Evaluation DOI Creative Commons
Samo Ribarič

Biomedicines, Год журнала: 2023, Номер 11(2), С. 355 - 355

Опубликована: Янв. 26, 2023

Early cognitive decline in patients with Alzheimer's (AD) is associated quantifiable structural and functional connectivity changes the brain. AD dysregulation of Aβ tau metabolism progressively disrupt normal synaptic function, leading to loss synapses, decreased hippocampal density early atrophy. Advances brain imaging techniques living have enabled transition from clinical signs symptoms-based diagnosis biomarkers-based diagnosis, techniques, quantitative EEG, body fluids sampling. The hippocampus has a central role semantic episodic memory processing. This function critically dependent on intrahippocampal connections many cortical regions, including perirhinal entorhinal cortex, parahippocampal association regions temporal parietal lobes, prefrontal cortex. Therefore, reflected altered intrinsic networks (aka large-scale networks), memory, default mode, salience networks. narrative review discusses recent critical issues related detecting AD-associated markers high-risk or neuropsychologically diagnosed subjective impairment mild impairment.

Язык: Английский

Процитировано

24
APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading DOI Creative Commons
Chanung Wang, Aishwarya Nambiar, Michael R. Strickland

и другие.

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(14)

Опубликована: Июнь 6, 2023

Alzheimer's disease (AD) is the most common cause of dementia. The APOE-ε4 allele apolipoprotein E (APOE) gene strongest genetic risk factor for late-onset AD. APOE genotype modulates effect sleep disruption on AD risk, suggesting a possible link between apoE and in pathogenesis, which relatively unexplored. We hypothesized that modifies Aβ deposition plaque-associated tau seeding spreading form neuritic plaque-tau (NP-tau) pathology response to chronic deprivation (SD) an isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with without AD-tau injection. found SD significantly increased peri-plaque NP-tau presence APOE4 but not APOE3. decreased microglial clustering around plaques aquaporin-4 (AQP4) polarization blood vessels also sleep-deprived APPPS1:E4 injected had altered behaviors compared APPPS1:E3 mice. These findings suggest critical modifier development SD.

Язык: Английский

Процитировано

24