Review on Alzheimer's disease: Inhibition of amyloid beta and tau tangle formation

Ashrafian, Hossein; Zadeh, Elaheh Hadi; Khan, Rizwan Hasan

doi:10.1016/j.ijbiomac.2020.11.192

Cited by 197 publications

(107 citation statements)

References 127 publications

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“…The postmortem brain anatomy of AD patients showed that there was more Aβ deposition and neurofibrillary tangles in the hippocampal region of the patients [95][96][97]. Moreover, by detecting the level of antioxidant protein in the hippocampus and amygdala, the level of oxidative stress in these two regions was found to be much higher than other regions.…”

Section: Effect Of Iron Metabolism Disorder On Admentioning

confidence: 95%

Iron Homeostasis Disorder and Alzheimer’s Disease

Peng

Chang

Lang

2021

IJMS

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Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer’s disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.

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Section: Effect Of Iron Metabolism Disorder On Admentioning

confidence: 95%

Iron Homeostasis Disorder and Alzheimer’s Disease

Peng

Chang

Lang

2021

IJMS

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“…Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder and is the most common cause of dementia in older people [ 1 , 2 ] Currently, over 50 million people worldwide are living with AD-related dementia, and this number is expected to increase to 152 million by 2050 (Alzheimer Association 2021). In addition to dementia, AD is associated with the loss of synapses [ 3 , 4 ], synaptic dysfunction [ 5 ], mitochondrial structural and functional abnormalities [ 6 , 7 , 8 ], microRNA deregulation [ 9 , 10 ], inflammatory responses [ 11 ], neuronal loss, accumulation of amyloid-beta (Aβ) [ 12 , 13 ] and phosphorylated tau (p-tau) [ 14 , 15 , 16 ]. Despite the progress that has been made in better understanding AD pathogenesis, researchers have still not identified early detectable markers, drugs, or agents that can prevent AD or slow its progression.…”

Section: Introductionmentioning

confidence: 99%

Early Cellular, Molecular, Morphological and Behavioral Changes in the Humanized Amyloid-Beta-Knock-In Mouse Model of Late-Onset Alzheimer’s Disease

Kshirsagar

Alvir

Hindle

et al. 2022

Cells

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The purpose of our study is to investigate early cellular, molecular, morphological and behavioral changes in humanized amyloid-beta-knock-in (hAbKI) mice. Using seven-month-old homozygous hAbKI mice, we studied behavioral phenotype parameters, including spatial learning and memory (Morris Water Maze), locomotor activity (open field), working memory (Y-maze) and motor coordination (rotarod); mRNA abundance, protein levels, soluble amyloid-beta 40 and 42 levels and regional immunoreactivities of key markers of mitochondrial dynamics, mitochondrial biogenesis, synaptic health, mitophagy and autophagy; mitochondrial function and using transmission electron microscopy & Golgi–Cox staining, we assessed mitochondrial morphology and dendritic spines. Our extensive behavioral analysis revealed that seven-month-old hAbKI mice showed impairments in motor coordination, reduced locomotor and exploration activities, impairments in working memory and spatial learning and memory. Our mRNA and protein analyses revealed the increased expression of mitochondrial-fission genes and reduced expression of mitochondrial-fusion, mitochondrial-biogenesis, synaptic, autophagy and mitophagy genes in seven-month-old hAbKI mice. An immunofluorescence analysis revealed altered immunoreactivities and agreed with the immunoblot results. Transmission-electron-microscopy data revealed increased mitochondrial fragmentation and reduced mitochondrial length in both hippocampal and cortical tissues of seven-month-old hAbKI mice and mitochondrial function defective. A Golgi–Cox-staining analysis revealed reduced dendritic spines in both cerebral cortices and hippocampi of hAbKI mice. Soluble amyloid-beta (1–40 and 1–42) were detected in three-month-old hAbKI mice and progressively increased in seven-month-old mice. These observations suggest that the human amyloid-beta peptide is sufficient to cause behavioral, mitochondrial, synaptic and ultrastructural changes in seven-month-old hAbKI mice. Our study findings also suggest that hAbKI mice might serve as a model for preclinical studies of preventive therapies.

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“…Gene mutations found in patients with familial AD facilitate Aβ production, which supports the Aβ hypothesis. As the overexpression of Aβ is a causal factor of AD, inhibiting the production and deposition of Aβ is considered as a therapeutic approach for AD 1 . However, except aducanumab, drug candidates in numerous clinical studies based on the Aβ theory have repeatedly failed to recover cognitive function 2,3 .…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle atrophy‐induced hemopexin accelerates onset of cognitive impairment in Alzheimer's disease

Nagase

Tohda

2021

J cachexia sarcopenia muscle

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Background Alzheimer's disease (AD) is an unmet medical need worldwide, and physical inactivity is a risk factor for AD. Performing physical exercise is difficult at old age, and thus, decline in physical movement may be a cause of age‐associated lowering of the brain function. This study aimed to elucidate the molecular mechanism and onset of the skeletal muscle atrophy‐induced acceleration of AD. Methods Pre‐symptomatic young 5XFAD or non‐transgenic wildtype mice were used. The bilateral hindlimbs were immobilized by placing them in casts for 14 days. Cognitive function was evaluated using the object recognition and spatial memory tests. Further, the hindlimb muscles were isolated for organ culture. Conditioned media (CM) of each muscle was separated by two‐dimensional polyacrylamide gel electrophoresis (2D‐PAGE). Protein expressions in the CM were analysed by matrix‐assisted laser desorption/ionization‐time‐of‐flight mass spectrometry analysis. The expression levels of candidate proteins were quantified using ELISA. After continuous intracerebroventricular (i.c.v.) infusion of recombinant hemopexin, cognitive function was evaluated. Gene microarray analysis of the hippocampus was performed to investigate the molecules involved in the accelerated memory deficit. Real‐time reverse transcription polymerase chain reaction and histological analysis confirmed the expression. Results Casting for 2 weeks reduced skeletal muscle weight. Object recognition memory in the cast‐attached 5XFAD mice (n = 7, training vs. test, P = 0.3390) was impaired than that in age‐matched wildtype (n = 7, training vs. test, P = 0.0523) and non‐cast 5XFAD mice (n = 7, training vs. test, P = 0.0473). On 2D‐PAGE, 88 spots were differentially expressed in muscle CM. The most increased spot in the cast‐attached 5XFAD CM was hemopexin. Hemopexin levels in the skeletal muscle (n = 3, P = 0.0064), plasma (n = 3, P = 0.0386), and hippocampus (n = 3, P = 0.0164) were increased in cast‐attached 5XFAD mice than those in non‐cast 5XFAD mice. Continuous i.c.v. infusion of hemopexin for 2 weeks induced memory deficits in young 5XFAD mice (n = 4, training vs. test, P = 0.6764). Lipocalin‐2 (Lcn2) messenger RNA (mRNA), neuroinflammation‐associated factor, was increased in the hippocampus in hemopexin‐infused 5XFAD mice than in control mice. LCN2 protein in the hippocampus was localized in the neurons, but not glial cells. Lcn2 mRNA levels in the hippocampus were also increased by cast‐immobilization of the hindlimbs (n = 6, P = 0.0043). Conclusions These findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.

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Review on Alzheimer's disease: Inhibition of amyloid beta and tau tangle formation

Cited by 197 publications

References 127 publications

Iron Homeostasis Disorder and Alzheimer’s Disease

Iron Homeostasis Disorder and Alzheimer’s Disease

Early Cellular, Molecular, Morphological and Behavioral Changes in the Humanized Amyloid-Beta-Knock-In Mouse Model of Late-Onset Alzheimer’s Disease

Skeletal muscle atrophy‐induced hemopexin accelerates onset of cognitive impairment in Alzheimer's disease

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