Effect and Mechanism of Rapamycin on Cognitive Deficits in Animal Models of Alzheimer’s Disease: A Systematic Review and Meta-analysis of Preclinical Studies DOI
Jie Cai,

Danni Xie,

Fanjing Kong

et al.

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 99(1), P. 53 - 84

Published: April 19, 2024

Background: Alzheimer’s disease (AD), the most common form of dementia, remains long-term and challenging to diagnose. Furthermore, there is currently no medication completely cure AD patients. Rapamycin has been clinically demonstrated postpone aging process in mice improve learning memory abilities animal models AD. Therefore, rapamycin potential be significant discovery development drugs for Objective: The main objective this systematic review meta-analysis was investigate effects mechanisms on by examining behavioral indicators pathological features. Methods: Six databases were searched 4,277 articles retrieved. In conclusion, 13 studies included according predefined criteria. Three authors independently judged selected literature methodological quality. Use subgroup analyses explore mechanistic interventions: AD, specific types transgenic models, dosage, periodicity administration. Results: results Morris Water Maze (MWM) test showed that escape latency shortened 15.60 seconds with therapy, indicating ability enhanced mice; number traversed platforms increased 1.53 times, improved significantly corrected deficits. CONCLUSIONS: therapy reduced age-related plaque deposition decreasing AβPP production down-regulating β-secretase γ-secretase activities, furthermore amyloid-β clearance promoting autophagy, as well tau hyperphosphorylation up-regulating insulin-degrading enzyme levels.

Language: Английский

Macrophages in health and disease DOI Creative Commons
Matthew D. Park,

Aymeric Silvin,

Florent Ginhoux

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(23), P. 4259 - 4279

Published: Nov. 1, 2022

Language: Английский

Citations

340
Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise DOI
Fei Yin

FEBS Journal, Journal Year: 2022, Volume and Issue: 290(6), P. 1420 - 1453

Published: Jan. 8, 2022

Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, a lack of disease‐modifying therapeutics. While the abnormal accumulation lipids was described in very first report AD neuropathology, it not until recent decades that lipid dyshomeostasis became focus research. Clinically, lipidomic metabolomic studies have consistently shown alterations levels various classes emerging early stages brains. Mechanistically, discovery research revealed multifaceted interactions between metabolism key pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, myelin degeneration. In present review, converging evidence defining summarized, followed by discussions on which contributes to pathogenesis modifies risk. Furthermore, lipid‐targeting therapeutic strategies, modification their efficacy stage, ApoE status, metabolic vascular profiles, are reviewed.

Language: Английский

Citations

193
Brain lipidomics: From functional landscape to clinical significance DOI Creative Commons
Jong Hyuk Yoon, Youngsuk Seo, Yeon Suk Jo

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(37)

Published: Sept. 16, 2022

Lipids are crucial components of cellular function owing to their role in membrane formation, intercellular signaling, energy storage, and homeostasis maintenance. In the brain, lipid dysregulations have been associated with etiology progression neurodegeneration other neurological pathologies. Hence, brain lipids emerging as important potential targets for early diagnosis prognosis diseases. This review aims highlight significance usefulness lipidomics diagnosing treating We explored alterations diseases, paying attention organ-specific characteristics functions lipids. As recent advances would impossible without analytical techniques, we provide up-to-date information on mass spectrometric approaches integrative analysis omic approaches. Last, present applications combined artificial intelligence techniques interdisciplinary collaborative research diseases clinical heterogeneities.

Language: Английский

Citations

148
Brain cell type-specific cholesterol metabolism and implications for learning and memory DOI
Dingfeng Li,

Juan Zhang,

Qiang Liu

et al.

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(5), P. 401 - 414

Published: Feb. 17, 2022

Language: Английский

Citations

92
Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease DOI Creative Commons
Vladimı́r Rudajev, Jiřı́ Novotný

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Aug. 25, 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder that one of the most devastating and widespread diseases worldwide, mainly affecting aging population. One key factors contributing to AD-related neurotoxicity production aggregation amyloid β (Aβ). Many studies have shown ability Aβ bind cell membrane disrupt its structure, leading death. Because damage affects different parts brain differently, it seems likely not only but also nature interface with which interacts, helps determine final neurotoxic effect. cholesterol dominant component plasma membrane, plays an important role in Aβ-induced toxicity. Elevated levels their regulation by statins been be influencing progression neurodegeneration. However, data from many has both neuroprotective aggravating effects relation development AD. In this review, we attempt summarize recent findings on toxicity mediated binding pathogenesis AD consider broader context lipid composition membranes.

Language: Английский

Citations

51
Metabolic perspective of astrocyte dysfunction in Alzheimer's disease and type 2 diabetes brains DOI Open Access
Zheng Shen, Zhengyang Li, Mengting Yu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 158, P. 114206 - 114206

Published: Jan. 5, 2023

The term type III diabetes (T3DM) has been proposed for Alzheimer's disease (AD) due to the shared molecular and cellular features between 2 (T2DM) insulin resistance-associated memory deficits cognitive decline in elderly individuals. Astrocytes elicit neuroprotective or deleterious effects AD progression severity. Patients with T2DM are at a high risk of impairment, targeting astrocytes might be promising alleviating neurodegeneration diabetic brain. Recent studies focusing on cell-specific activities brain have revealed important role metabolism (e.g., glucose metabolism, lipid metabolism), neurovascular coupling, synapses, synaptic plasticity. In this review, we discuss how their dysfunction result multiple pathological clinical from metabolic perspective potential comorbid mechanism these two diseases astrocytes.

Language: Английский

Citations

33
Cholesterol Metabolism in Aging and Age-Related Disorders DOI Creative Commons
Gesine Saher

Annual Review of Neuroscience, Journal Year: 2023, Volume and Issue: 46(1), P. 59 - 78

Published: July 10, 2023

All mammalian cell membranes contain cholesterol to maintain membrane integrity. The transport of this hydrophobic lipid is mediated by lipoproteins. Cholesterol especially enriched in the brain, particularly synaptic and myelin membranes. Aging involves changes sterol metabolism peripheral organs also brain. Some those alterations have potential promote or counteract development neurodegenerative diseases during aging. Here, we summarize current knowledge general principles humans mice, most widely used model organism biomedical research. We discuss that occur aged brain highlight recent developments type-specific fast-growing research field aging age-related diseases, focusing on Alzheimer's disease. propose handling interplay between types critically influence disease processes.

Language: Английский

Citations

33
Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy DOI Creative Commons
Danira Toral-Ríos, Justin M. Long, Jason D. Ulrich

et al.

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(4)

Published: March 1, 2024

Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation changes brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation metabolism, produced cholesterol 25-hydroxylase encoded Ch25h expressed as “disease-associated microglia” signature gene. However, whether influences tau-mediated neurodegeneration unknown. Here, we show that the absence resultant reduction 25-HC, there strikingly reduced age-dependent hippocampus entorhinal/piriform cortex PS19 mice, which express P301S mutant human tau transgene. Transcriptomic analyses bulk hippocampal tissue single nuclei revealed deficiency mice strongly suppressed proinflammatory signaling microglia. Our results suggest key role for Ch25h/25-HC potentiating promote neurodegeneration. may represent novel therapeutic target primary tauopathies, AD, other neuroinflammatory diseases.

Language: Английский

Citations

13
Cholesterol imbalance and neurotransmission defects in neurodegeneration DOI Creative Commons
Kyung Chul Shin,

Houda Yasmine Ali Moussa,

Yongsoo Park

et al.

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(8), P. 1685 - 1690

Published: Aug. 1, 2024

The brain contains the highest concentration of cholesterol in human body, which emphasizes importance physiology. Cholesterol is involved neurogenesis and synaptogenesis, age-related reductions levels can lead to synaptic loss impaired plasticity, potentially contribute neurodegeneration. maintenance homeostasis neuronal plasma membrane essential for normal function, imbalances distribution are associated with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's Huntington's disease. This review aims explore molecular pathological mechanisms by imbalance neurotransmission defects neurodegeneration, focusing on four key mechanisms: (1) dysfunction, (2) alterations structure protein clustering, (3) oligomers amyloid beta (Aβ) protein, (4) α-synuclein aggregation.

Language: Английский

Citations

12
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice DOI Creative Commons
María Latorre‐Leal, Patricia Rodriguez‐Rodriguez,

Luca Franchini

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(4)

Published: Jan. 24, 2024

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting into 24 S -hydroxycholesterol (24OH). Dysregulation of brain and reduced levels are observed in Alzheimer’s disease (AD). In this study, we report that overexpression aged female mice leads to enhanced estrogen signaling the hippocampus improved cognitive functions. contrast, age-matched overexpressing males show anxiety-like behavior, worsened memory, elevated 5α-dihydrotestosterone hippocampus. We that, neurons, 24OH contributes these divergent effects activating sex hormone signaling, including receptors. protects from memory impairments induced ovariectomy while having no gonadectomized males. Last, measured cerebrospinal fluid a clinical cohort patients with AD found negatively correlates neurodegeneration markers only women. suggest activation is valuable pharmacological target for enhancing women at risk developing neurodegenerative diseases.

Language: Английский

Citations

9