A Unified Hypothesis of Early- and Late-Onset Alzheimer’s Disease Pathogenesis

Atwood, Craig S.; Bowen, Richard L.

doi:10.3233/jad-143210

Cited by 47 publications

(29 citation statements)

References 169 publications

(170 reference statements)

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“…Conversely, NMD activator therapy could provide clinical benefit for neural diseases in which autophagy is abnormally elevated [165]. Signaling pathways are also known to be dysregulated in several neurodegenerative diseases [166–168], which is interesting in light of the recent work demonstrating that the NMD pathway regulates TGF-β signaling and possibly Wnt and Notch signaling [28, 29]. This raises the possibility that NMD activation or inhibition therapy that reverses dysregulated signaling in neurodegenerative disease could provide clinical benefit.…”

Section: Perspectivesmentioning

confidence: 99%

Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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Cells respond to internal and external cellular stressors by activating stress response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly-conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway—Nonsense-Mediated RNA Decay (NMD)—serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that “NMD therapy” may provide clinical benefit by downmodulating stress responses.

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Section: Perspectivesmentioning

confidence: 99%

Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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“…Evidence also suggests the regulation of the transcription factor EGR-1 may be regulated by APP, which may play a role in AD development and memory formation [265]. Mutations in NRF1 targets PSEN1 and PSEN2 may also lead to the development of neurodegenerative disease [266,267,268]. In addition PSEN1 and PSEN2 transcription, expression, promoter activity, and mRNA levels are influenced by the PARKIN protein [269].…”

Section: Mechanisms Of Actions Of Estrogenic Endocrine Disruptors mentioning

confidence: 99%

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

Preciados

Yoo

Roy

2016

IJMS

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During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD—APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF—underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely ...

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“…However, sporadic AD attracts the most interest now, since it is not related to mutations observed in familial cases of AD. In addition to increased Aβ lev els, sporadic AD is characterized by synaptic dysfunc tions, massive death of neurons in the neocortex and hip pocampus, and cell cycle deterioration [2]. Patients with sporadic AD display impaired mitochondrial energy metabolism, in particular, decreased activity of cytochrome c oxidase resulting from low enzyme expres sion and/or insufficient number of subunits of the com plex [24,28].…”

Section: Discussionmentioning

confidence: 99%

“…AD is characterized by memory loss and dementia that accompany brain atrophy, ultimately lead ing to the patient's death. Major morphological features of AD are extracellular accumulation of the fibrillar beta amyloid protein (Aβ) in cortical senile plaques and intra neuronal formation of neurofibrillary tangles from phos phorylated tau protein [1,2]. Unlike hereditary AD, spo radic AD is the clinically predominant form with mostly late onset.…”

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confidence: 99%

Mitochondrial dysfunction in neocortex and hippocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease

Avetisyan

Samokhin

Alexandrova

et al. 2016

Biochemistry Moscow

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Structural and functional impairments of mitochondria in brain tissues in the pathogenesis of Alzheimer's disease (AD) cause energy deficiency, increased generation of reactive oxygen species (ROS), and premature neuronal death. However, the causal relations between accumulation of beta-amyloid (Aβ) peptide in mitochondria and mitochondrial dysfunction, as well as molecular mechanisms underlying deleterious effects of both these factors in sporadic AD, the most common form in humans, remain unknown. Here we used olfactory bulbectomized (OBX) mice of NMRI strain as a model for sporadic AD. Five weeks after surgery, the OBX mice developed major behavioral and biochemical features of AD neurodegeneration, including spatial memory loss, increased brain levels of Aβ, and energy deficiency. Mitochondria isolated from the neocortex and hippocampus of OBX mice displayed severe functional impairments, such as low NADH oxidation rate, reduced transmembrane potential, and decreased cytochrome c oxidase (complex IV) activity that correlated with high levels of soluble Aβ1-40. Mitochondria from OBX mice showed increased contents of lipid peroxidation products, indicative of the development of oxidative stress. We found that neurodegeneration caused by olfactory bulbectomy is accompanied by energy metabolism disturbances and oxidative stress in brain mitochondria similar to those occurring in transgenic animals - familial AD models and patients with sporadic AD. Therefore, OBX mice can serve as a valid AD model for investigating the mechanisms of AD neurodegeneration, drug testing, and development of therapeutic strategies for AD treatment.

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A Unified Hypothesis of Early- and Late-Onset Alzheimer’s Disease Pathogenesis

Cited by 47 publications

References 169 publications

Stress and the nonsense-mediated RNA decay pathway

Stress and the nonsense-mediated RNA decay pathway

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

Mitochondrial dysfunction in neocortex and hippocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease

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