scholarly journals Tip60 protects against amyloid-β peptide-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegenerative progression

2020 ◽  
Author(s):  
Haolin Zhang ◽  
Bhanu Chandra Karisetty ◽  
Akanksha Bhatnagar ◽  
Ellen M. Armour ◽  
Mariah Beaver ◽  
...  
Keyword(s):  
Cell Death ◽  
Cognitive Deficits ◽  
Late Stage ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Peptide ◽  
Histone Deacetylase 2 ◽  
Age Related ◽  
Late Stages

ABSTRACTAlzheimer’s disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-β42. We show that early Aβ42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the Aβ42 fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.

scholarly journals Apoptotic Neuronal Cell Death Induced by the Non-fibrillar Amyloid-β Peptide Proceeds through an Early Reactive Oxygen Species-dependent Cytoskeleton Perturbation

2002 ◽  
Vol 278 (5) ◽  
pp. 3437-3445 ◽  
Author(s):  
Isabelle Sponne ◽  
Alexandre Fifre ◽  
Béatrice Drouet ◽  
Christophe Klein ◽  
Violette Koziel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Reactive Oxygen ◽  
Amyloid Β Peptide ◽  
Oxygen Species

scholarly journals Idebenone attenuates amyloid β-peptide-induced cell death in rat hippocampal neuronal cell cultures

1997 ◽  
Vol 73 ◽  
pp. 245
Author(s):  
Hitomi Hayako ◽  
Keisuke Hirai ◽  
Koki Kato ◽  
Masaomi Miyamoto
Keyword(s):  
Cell Death ◽  
Cell Cultures ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Peptide ◽  
Neuronal Cell Cultures

The Nonfibrillar Amyloid β-Peptide Induces Apoptotic Neuronal Cell Death

2002 ◽  
Vol 73 (4) ◽  
pp. 1626-1634 ◽  
Author(s):  
Thierry Pillot ◽  
Béatrice Drouet ◽  
Sophie Queillé ◽  
Christine Labeur ◽  
Joël Vandekerckhove ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Peptide

Visualization of co-localization in Aβ42-administered neuroblastoma cells reveals lysosome damage and autophagosome accumulation related to cell death

2011 ◽  
Vol 441 (2) ◽  
pp. 579-590 ◽  
Author(s):  
Violetta Soura ◽  
Maris Stewart-Parker ◽  
Thomas L. Williams ◽  
Arjuna Ratnayaka ◽  
Joe Atherton ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Function ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Immunogold Electron Microscopy ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Oligomeric Form ◽  
Endosomal System

Aβ42 [amyloid-β peptide-(1–42)] plays a central role in Alzheimer's disease and is known to have a detrimental effect on neuronal cell function and survival when assembled into an oligomeric form. In the present study we show that administration of freshly prepared Aβ42 oligomers to a neuroblastoma (SH-SY5Y) cell line results in a reduction in survival, and that Aβ42 enters the cells prior to cell death. Immunoconfocal and immunogold electron microscopy reveal the path of the Aβ42 with time through the endosomal system and shows that it accumulates in lysosomes. A 24 h incubation with Aβ results in cells that have damaged lysosomes showing signs of enzyme leakage, accumulate autophagic vacuoles and exhibit severely disrupted nuclei. Endogenous Aβ is evident in the cells and the results of the present study suggest that the addition of Aβ oligomers disrupts a crucial balance in Aβ conformation and concentration inside neuronal cells, resulting in catastrophic effects on cellular function and, ultimately, in cell death.

scholarly journals Effect of policosanol from insect wax on amyloid β-peptide-induced toxicity in a transgenic Caenorhabditis elegans model of Alzheimer’s disease

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xin Zhang ◽  
Chenjing Ma ◽  
Long Sun ◽  
Zhao He ◽  
Ying Feng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caenorhabditis Elegans ◽  
Life Span ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Health Concern ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

Abstract Background Alzheimer’s disease (AD), an age-related neurodegenerative disorder and a serious public health concern, is mainly caused by β-amyloid (Aβ)-induced toxicity. Currently, a limited number of drugs are effective against AD, and only a few are used for its treatment. According to traditional Chinese medicine, white wax is mainly composed of policosanol, hexacosanol, and octacosanol. Policosanol has been shown to reduce lipid levels in blood and alleviate the symptoms associated with diabetic complications and neurodegenerative disorders, such as Parkinson’s disease and AD. However, the efficacy of policosanol depends on the purity and composition of the preparation, and the therapeutic efficacy of policosanol derived from insect wax (PIW) in AD is unknown. Methods Here, we identified the main components of PIW and investigated the effects of PIW on Aβ-induced toxicity and life-span in a transgenic Caenorhabditis elegans model of AD, CL4176. Furthermore, we estimated the expression of amyloid precursor-like protein (apl-1) and the genes involved in various pathways associated with longevity and alleviation of AD-related symptoms in PIW-fed CL4176. Results PIW mainly consists of tetracosanol, hexacosanol, octacosanol, and triacontanol; it could decrease the Aβ-induced paralysis rate from 86.87 to 66.97% (P < 0.01) and extend the life-span from 6.2 d to 7.8 d (P < 0.001) in CL4176 worms. Furthermore, PIW downregulated apl-1, a gene known to be associated with the levels of Aβ deposits in C. elegans. Additionally, our results showed that PIW modulated the expression of genes associated with longevity-related pathways such as heat shock response, anti-oxidative stress, and glutamine cysteine synthetase. Conclusion Our findings suggest that PIW may be a potential therapeutic agent for the prevention and treatment of AD. However, its effects on murine models and patients with AD need to be explored further.

scholarly journals The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 900
Author(s):  
Sergey Shityakov ◽  
Kentaro Hayashi ◽  
Stefan Störk ◽  
Verena Scheper ◽  
Thomas Lenarz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
The Elderly ◽  
Amyloid Β Peptide ◽  
Age Related ◽  
Amyloid Cardiomyopathy ◽  
Age Related Hearing Loss

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease.

Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

scholarly journals Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

2021 ◽  
Vol 6 (1) ◽  
pp. e000774
Author(s):  
Minwei Wang ◽  
Shiqi Su ◽  
Shaoyun Jiang ◽  
Xinghuai Sun ◽  
Jiantao Wang
Keyword(s):  
Mitochondrial Dysfunction ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Cell Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Amyloid Β Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

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