Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders

AbstractAging is an important risk factor for several human diseases such as cancer, cardiovascular disease and neurodegenerative disorders, resulting from a combination of genetic and environmental factors (e.g., diet, smoking, obesity and stress), which, at molecular level, cause changes in gene expression underlying the decline of physiological function. Epigenetics, which include mechanisms regulating gene expression independently of changes to DNA sequence, regulate gene expression by modulating the structure of chromatin or by regulating the binding of transcriptional machinery to DNA. Several studies showed that an impairment of epigenetic mechanisms promotes alteration of gene expression underlying several aging-related diseases. Alteration of these mechanisms is also linked with changes of gene expression that occurs during aging processes of different tissues. In this review, we will outline the potential role of epigenetics in the onset of two age-related pathologies, cancer and cardiovascular diseases.

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Cytoplasmic mislocalization and mitochondrial colocalization of TDP-43 are common features between normal aged and young mice

Experimental Biology and Medicine ◽

10.1177/1535370220914253 ◽

2020 ◽

Vol 245 (17) ◽

pp. 1584-1593 ◽

Cited By ~ 1

Author(s):

Pichet Termsarasab ◽

Thananan Thammongkolchai ◽

Ju Gao ◽

Luwen Wang ◽

Jingjing Liang ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Neuronal Loss ◽

Critical Factor ◽

Brain Regions ◽

Normal Aging ◽

Age Related ◽

Wide Range ◽

Cytoplasmic Accumulation ◽

Young Mice

Transactive response DNA binding protein 43 (TDP-43) pathologies have been well recognized in various neurodegenerative disorders including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). However, there have been limited studies on whether there are any TDP-43 alterations in normal aging. We investigated TDP-43 distribution in different brain regions in normal aged ( n = 3 for 26- or 36-month-old) compared to young ( n = 3 for 6- or 12-month-old) mice. In both normal aged and young mice, TDP-43 and phosphorylated TDP-43 (pTDP-43) demonstrated a unique pattern of distribution in neurons in some specific brain regions including the pontine nuclei, thalamus, CA3 region of the hippocampus, and orbital cortex. This pattern was demonstrated on higher magnification of high-resolution double fluorescence images and confocal microscopy as mislocalization of TDP-43 and pTDP-43, characterized by neuronal nuclear depletion and cytoplasmic accumulation in these brain regions, as well as colocalization between TDP-43 or pTDP-43 and mitochondria, similar to what has been described previously in neurodegenerative disorders. All these findings were identical in both normal aged and young mice. In summary, TDP-43 and pTDP-43 mislocalization from nucleus to cytoplasm and their colocalization with mitochondria in the specific brain regions are present not only in aging, but also in young healthy states. Our findings provide a new insight for the role of TDP-43 proteinopathy in health and diseases, and that aging may not be a critical factor for the development of TDP-43 proteinopathy in subpopulations of neurons. Impact statement Despite increasing evidence implicating the important role of TDP-43 in the pathogenesis of a wide range of age-related neurodegenerative diseases, there is limited study of TDP-43 proteinopathy and its association with mitochondria during normal aging. Our findings of cytoplasmic accumulation of TDP-43 that is highly colocalized with mitochondria in neurons in selective brain regions in young animals in the absence of neuronal loss provide a novel insight into the development of TDP-43 proteinopathy and its contribution to neuronal loss.

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Vitamins and Cognition: A Nutrigenomics Perspective

Current Nutrition & Food Science ◽

10.2174/1573401316999200901180443 ◽

2020 ◽

Vol 16 ◽

Author(s):

Ayyappan Anitha ◽

Vijitha Viswambharan ◽

Ismail Thanseem ◽

Mary Iype ◽

Rahna Parakkal ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Cognitive Functions ◽

Cognitive Impairments ◽

Cognitive Disorders ◽

Therapeutic Strategies ◽

Epigenetic Factors ◽

Future Studies ◽

Age Related ◽

Novel Approaches

: The rise in the prevalence of neurodegenerative and neurodevelopmental cognitive disorders combined with a lack of efficient therapeutic strategies has necessitated the need to develop alternate approaches. Dietary supplements are now being considered as a complementary and alternative medicine for cognitive impairments. Considerable evidence suggests the role of vitamins in modulating the genetic and epigenetic factors implicated in neuropsychiatric, neurodevelopmental and neurodegenerative disorders. In this review, we provide an overview on the implications of nutrigenomics with reference to vitamins that are suggested to boost cognitive functions (nootropic vitamins). Several vitamins have been found to possess antioxidant and anti-inflammatory properties which make them potential candidates in preventing or delaying age-related neurodegeneration and cognitive decline. Well-designed longitudinal studies are essential to examine the association between vitamins and cognitive functions. Future studies linking nutrition with advances in neuroscience, genomics and epigenomics would provide novel approaches to the management of cognitive disorders.

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It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/2756068 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 43

Author(s):

Antonella Tramutola ◽

Fabio Di Domenico ◽

Eugenio Barone ◽

Marzia Perluigi ◽

D. Allan Butterfield

Keyword(s):

Oxidative Stress ◽

Alzheimer Disease ◽

Ubiquitin Proteasome System ◽

Oxidative Modification ◽

Age Related ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

And Function ◽

Cellular Components

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

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Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease

Revue Neurologique ◽

10.1016/j.neurol.2019.08.005 ◽

2019 ◽

Vol 175 (10) ◽

pp. 724-741 ◽

Cited By ~ 24

Author(s):

G.C. Román ◽

R.E. Jackson ◽

R. Gadhia ◽

A.N. Román ◽

J. Reis

Keyword(s):

Fatty Acids ◽

Alzheimer Disease ◽

Cognitive Decline ◽

Mediterranean Diet ◽

Age Related ◽

Age Related Cognitive Decline ◽

Long Chain

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The Neuromelanin Paradox and Its Dual Role in Oxidative Stress and Neurodegeneration

Antioxidants ◽

10.3390/antiox10010124 ◽

2021 ◽

Vol 10 (1) ◽

pp. 124

Author(s):

Alexandra Moreno-García ◽

Alejandra Kun ◽

Miguel Calero ◽

Olga Calero

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Neurodegenerative Disorders ◽

Normal Aging ◽

Saturation State ◽

Neurodegenerative Process ◽

Age Related ◽

Extracellular Release ◽

Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, xenobiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and neurodegeneration related to its capabilities as an antioxidant and scavenging of harmful molecules, versus its involvement in oxidative stress and aberrant immune response, depending on NM saturation state and its extracellular release.

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Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders

Pharmacological Research ◽

10.1016/j.phrs.2011.04.007 ◽

2011 ◽

Vol 64 (3) ◽

pp. 180-186 ◽

Cited By ~ 50

Author(s):

D. Allan Butterfield ◽

Eugenio Barone ◽

Cesare Mancuso

Keyword(s):

Alzheimer Disease ◽

Neurodegenerative Disorders ◽

Age Related ◽

Statin Use

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The Neuromelanin Paradox and its Dual Role in Oxidative Stress and Neurodegeneration

10.20944/preprints202012.0033.v1 ◽

2020 ◽

Author(s):

Alexandra Moreno García ◽

Alejandra Kun ◽

Miguel Calero Lara ◽

Olga Calero

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Neurodegenerative Disorders ◽

Normal Aging ◽

Saturation State ◽

Neurodegenerative Process ◽

Age Related ◽

Extracellular Release ◽

Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, antibiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and catecholaminergic metabolism due to its capability as a pro-oxidant and other harmful molecules, versus its involvement in oxidative stress and aberrant immune response, which it is highly dependent on NM saturation state and its extracellular release.

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HYPERTENSION DOES NOT CONTRIBUTE TO MICROBLEEDS ONSET IN FEMALE EFAD MICE

Innovation in Aging ◽

10.1093/geroni/igz038.352 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S93-S93

Author(s):

Mafalda Cacciottolo ◽

Todd E Morgan ◽

Caleb E Finch

Keyword(s):

Blood Pressure ◽

Alzheimer Disease ◽

Mouse Model ◽

Age Changes ◽

Clinical Burden ◽

Longitudinal Measurements ◽

Age Related ◽

Amyloid Deposits ◽

Tail Cuff

Abstract Cerebral microbleeds (MBs) contribute to pre-clinical cognitive decline and are an additional clinical burden in Alzheimer Disease (AD). Hypertension is associated with MBs, with nearly 2-fold higher likelihood for MBs per SD increment in blood pressure (BP). We investigated the possible role of age-related hypertension in the EFAD mouse model (transgenic for carrying familial AD mutations and targeted replacement of human APO-E3 or -E4). MBs were detected by Prussian Blue histochemistry. We extended prior findings with observations that MBs arise early in life, by 2 months, and confirmed female excess for ApoE3 and-E4 carriers. Wildtype C57BL/6J mice also accumulated MBs, and a 10-fold lower level and more slowly up to 21mo of age. BP was measured by the tail-cuff method. All mice had BP in the normotensive range, <150 mm Hg, systolic. Longitudinal measurements of blood pressure at ages 2, 4, and 6 months showed few age changes, except for E3FAD females at 6 months (systolic, +20%, p<0.05; diastolic, +33%, p<0.05). A possible decrease in blood pressure was observed in EFAD mice (-33%, p<0.01) compared to C57BL/6J mice. A not statistical trend of increase was observed in older C57BL/6J mice up to 18 mo of age, consistent with previous reports. Older ages are required for complete negation of role of hypertension in the MB model. Ongoing studies will examine mice older than 6 months for potential relations of blood pressure and MB, and in relation to brain amyloid deposits which surrounded MBs in our prior study.

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