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Age-associated neurodegenerative diseases

Age-associated neurodegenerative diseases


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Age-associated neurodegenerative diseases encompass Alzheimer's Disease and Parkinson's Disease. What other neurodegenerative diseases could be described as age-associated? Multiple Sclerosis? Brain tumors? What might be the criteria for defining a disease as age-associated, specifically in the realm of neurobiology?


Dementia with Lewy bodies (DLB): It is characterized anatomically by the presence of Lewy bodies, clumps of alpha-synuclein and ubiquitin protein in neurons, detectable in post-mortem brain histology.[1] Lewy Body dementia affects 1.3 million individuals in the United States alone.

http://en.wikipedia.org/wiki/Dementia_with_Lewy_bodies

Binswanger disease is a form of small vessel vascular dementia caused by damage to the white brain matter.[1] White matter atrophy can be caused by many circumstances including chronic hypertension as well as old age.[2] This disease is characterized by loss of memory and intellectual function and by changes in mood. These changes encompass what are known as executive functions of the brain.[3] It usually presents between 54 and 66 years of age, and the first symptoms are usually mental deterioration or stroke.[4]

http://en.wikipedia.org/wiki/Binswanger%27s_disease

To name the two with the highest prevalence after Alzheimer's and Parkinson's.


Rebooting Regeneration Alzheimer’s Disease

Alzheimer’s disease (AD) is the leading age-associated neurodegenerative disease, affecting more than 50 million people globally. No therapies exist to prevent, delay or treat AD. Current therapies provide modest short-term benefit while not affecting disease progression. Alzheimer’s is a complex neurodegenerative disease that typically develops over the course of a decade or more. The hallmark pathologies of AD are decline in brain glucose metabolism and mitochondrial function, beta amyloid plaques, neurofibrillary tangles, inflammation and brain atrophy. The Alzheimer’s risk gene, ApoE4, can accelerate and exacerbate the course of the disease.

By focusing on those most affected by Alzheimer’s, women, we discovered that the brain undergoes a series of transitions starting early in the aging process that spans years during the pre-clinical or prodromal stage of AD. The long road to age-associated Alzheimer’s starts with a rise in brain inflammation and concomitant decline in glucose metabolism followed by development of the hallmark pathologies of Alzheimer’s.


P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes?

Neurodegenerative diseases are a heterogeneous, mostly age-associated group of disorders characterized by progressive neuronal loss, the most prevalent being Alzheimer disease. It is anticipated that, with continuously increasing life expectancy, these diseases will pose a serious social and health problem in the near feature. Meanwhile, however, their etiology remains largely obscure even though all possible novel clues are being thoroughly examined. In this regard, a concept has been proposed that p53, as a transcription factor controlling many vital cellular pathways including apoptosis, may contribute to neuronal death common to all neurodegenerative disorders. In this work, we review the research devoted to the possible role of p53 in the pathogenesis of these diseases. We not only describe aberrant changes in p53 level/activity observed in CNS regions affected by particular diseases but, most importantly, put special attention to the complicated reciprocal regulatory ties existing between p53 and proteins commonly regarded as pathological hallmarks of these diseases, with the ultimate goal to identify the primary element of their pathogenesis.

Keywords: Alzheimer disease Parkinson disease apoptosis neurodegenerative diseases neuronal loss p53.


New pathway is a common thread in age-related neurodegenerative diseases

La Jolla, CA–How are neurodegenerative diseases such as Alzheimer’s initiated, and why is age the major risk factor? A recent study of a protein called MOCA (Modifier of Cell Adhesion), carried out at the Salk Institute for Biological Studies, provides new clues to the answers of these fundamental questions.

Under normal circumstances, MOCA is a key member of the squadron charged with keeping Alzheimer’s disease at bay. A team of researchers led by Salk professor David Schubert, Ph.D., demonstrated what happens when MOCA goes on furlough. In the process Schubert identified a novel pathway with broad implications for both Alzheimer’s and other age-related neurodegenerative diseases.

Over time, protein aggregates (shown in green) accumulate in the axons of MOCA-deficient mice. They start out small, initially causing few or no symptoms, but as they built up in the axons, they begin to destroy the cytoskeleton, the internal framework of the cells, increasingly interfering with the transmission of signals from the nerve cells. Eventually the affected axons die, followed by the death of the nerve cell itself.

Image: Courtesy of Dr. Qi Chen, Salk Institute for Biological Studies.

Their findings, reported in the current issue of the Journal of Neuroscience, show how neurodegenerative disease starts, initiating in the nerve ending and inducing gradual changes, like a chain reaction over a long time. The animal model used in the study also will allow scientists to better understand the processes behind the formation of the protein aggregates that are common to most neurodegenerative diseases. In addition, it will provide new opportunities to target the earliest steps for therapy.

MOCA was initially identified as a protein that binds to presenilin, a molecule that when mutated causes familial Alzheimer’s disease. MOCA is only found in neurons and regulates the expression of the beta amyloid protein responsible for the Alzheimer’s plaques that are the hallmark of the disease. To better understand MOCA’s function, Qi Chen, Ph.D., a senior scientist in Schubert’s laboratory, created a line of mice genetically engineered to lack the gene for MOCA.

“Because of the initial studies in cultured cells that we had done, we expected these mice to develop plaques,” explains Schubert. “What we found was that they develop ataxia–a motor coordination problem–as they age.” Chen then studied the pathology of these mice and found that it reflected a common feature of most age-related neurological diseases, not just Alzheimer’s.

The main problem turned out to be the degeneration of axons, the long projections that conduct impulses away from neurons. The axonal degeneration was caused by the accumulation of protein aggregates. Although the mice were not born with the problem, they acquired it, along with the ataxia, as they aged, and the ataxia worsened over time.

The aggregates started out small, initially causing few or no symptoms, but as they built up in the axons, they began to destroy the cytoskeleton, the internal framework of the cells, increasingly interfering with the transmission of signals from the nerve cells. Eventually the affected axons died, followed by the death of the nerve cell itself.

“Protein aggregates are common features of most age-related neurological diseases,” says Chen, the first author of the study. “So is axon degeneration we see it in Alzheimer’s, ALS, and Huntington’s disease. Motor problems such as ataxia may be the most obvious manifestation because the aggregates appear in the long axons of the spinal cord. But the axonal aggregates also appear in the brain and may be the first step in the events that lead to age-associated neurological disease.”

After documenting the sequence of physiological and behavioral events that characterize the axon degeneration, Chen then sought to piece together the molecular pathway behind it, starting with MOCA and connecting findings from disparate studies that previously had identified parts of the pathway. He ended up with a single, step-by-step process for axon degeneration that for the first time linked together a number of diseases and conditions, including a form of mental retardation in humans.

“We had known that MOCA affected the cytoskeleton for some time, but no one had put together clear evidence showing how the sequential age-associated changes in the cytoskeleton of the nerve take place. Dr. Chen was able to do this, thereby connecting the disease pathology with the molecular biology,” says Schubert. “Now we know that MOCA is essential to the functional integrity of axons and have defined a complete pathway for axon degeneration.”

The study was funded with support from the National Institutes of Health, the Bundy Foundation, the Alzheimer’s Association, and the Shirley Foundation for Alzheimer’s Research.


Molecular Mechanisms of Mitophagy

Mitophagy shares the core molecular machinery with general macroautophagy and can occur in an either selective or non-selective fashion (Levine and Kroemer, 2019). Thus, during nutrient starvation mitochondria were found in autophagosomes together with cytosolic proteins and organelles such as ER and peroxisomes indicative for non-selective mitophagy (Kopitz et al., 1990 Takeshige et al., 1992 Scott and Klionsky, 1998 Kim et al., 2007 Figure 1). Studies in yeast revealed that mitochondria can be selectively degraded by mitophagy, a process that involves the outer mitochondrial membrane protein SUN family protein Uth1 (Uth1), and type 2C protein phosphatase Ptc6 (Ptc6, better known as Aup1), a phosphatase localizing in the mitochondrial intermembrane space (Petros et al., 1991 Kissova et al., 2004). Mitophagy has been shown to occur under a series of potentially harmful conditions, such as oxidative stress, hypoxia, mitochondrial transmembrane potential loss, the accumulation of unfolded proteins and iron starvation. Moreover, impaired mitophagy and dysfunctional mitophagic mechanisms were associated with numerous physiological and pathological processes including development, differentiation, aging, neurodegenerative disorders, cardiovascular pathologies and cancer.

Figure 1. Non-selective mitophagy. Mitophagy shares the core molecular machinery with general macroautophagy and can occur in a non-selective fashion. Thus, mitochondria are engulfed during the nucleation and elongation phase into the forming phagophore together with other cellular content such as protein aggregates, endoplasmic reticulum (ER) derived structures and invasive bacteria. The fusion of the phagosome with lysosomes leads to the formation of the autophagolysosome and the degradation of its content.


June 7-9, 2021 | 9:00AM EDT | 1:00PM UTC | 3:00PM CEST*
*Program is in development and subject to change

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Neurodegenerative diseases, such as Alzheimer’s disease (AD) and AD-related disorders (ADRD) are quickly becoming a global burden. The number of diagnosed cases of neurodegenerative diseases is staggering and rising at an alarming rate as the population ages. While it is well-recognized that neurodegenerative diseases are characterized by aberrant protein misfolding and aggregate formation, the mechanisms that initiate or promote proteinopathy in disease-specific neural circuits remain poorly understood. Recent advances in human genetics and genome-wide association study (GWAS) have uncovered several genetic loci that are critical for the pathogenesis of neurodegenerative diseases. Furthermore, technological advances in transcriptomics, proteomics, and metabolomics offer many critical new insights into the disease mechanism, as well as opportunities for the development of novel therapeutics that can reverse or mitigate neurodegeneration. Despite these exciting new developments, there are significant gaps in connecting genetic information with disease mechanism and in harnessing the critical role of glia-neuron interactions to develop therapeutic interventions.

This conference aims to provide an integrated discussion of the latest advances in research and therapeutic development for neurodegenerative diseases. This conference program will focus on the roles of genetic risk factors and their contributions to glial and neuronal health in the aging brain, the biophysical properties of protein misfolding and the propagation of disease-specific proteinopathy, the role of intracellular vesicular trafficking in disease pathogenesis, new insights into the diverse role of glia, innate immunity and microbiomes in neurodegeneration, and novel therapeutic approaches that specifically target each of the novel biological areas. It is anticipated that this conference will stimulate more discussions and promote new collaborations among scientists in the academia and industry that ultimately lead to new therapeutic targets to combat neurodegenerative diseases.

Pricing:

Regular Registration Rate: $275 USD
Student Registration Rate: $150 USD

Deadlines:

Abstract Submission
‣ For Short Talk Consideration: Passed
‣ For ePoster Presentation: Passed
Final ePoster / SciTalk Submission: Passed
Financial Aid Application: Passed

*Abstract submission is required in order to submit an ePoster and/or Scitalk


Doc Talks: Aging for Life – Dodging Neurodegenerative Diseases

Co-sponsored by the College of Medicine – Tucson and Banner Health, Doc Talks is a free health lecture series for the Tucson community.

On Tuesday, Sept. 25, Roberta Brinton, PhD, will present the last of four free lectures as part of the Doc Talks series. Dr. Roberta Diaz Brinton is an innovative and creative neuroscientist whose early insights led to the leadership position she holds today in the field of Alzheimer’s, the aging female brain and regenerative therapeutics to prevent, delay and treat the disease. More than 20 years ago, Dr. Brinton had two fundamental insights that have, after years of research, yielded major breakthroughs in understanding the etiology of Alzheimer’s and therapeutics to prevent, delay and treat the disease. Her insights, which predated the advent of precision medicine, formed the basis for programs of research that are critical to personalized therapeutic care for Alzheimer’s disease. Dr. Brinton is currently the Director of the UA Center for Innovation in Brain Science and a professor of pharmacology and neurology at the College of Medicine – Tucson.

Dr. Brinton's lecture, "Aging for Life," will focus on age-associated neurodegenerative diseases. In the 21st century there is not a single cure for a single neurodegenerative disease. While therapies exist, they provide symptom relief while the degenerative process marches ever forward. The University of Arizona Center for Innovation in Brain Science is tackling this challenge. Age is the greatest risk factor for Alzheimer’s, Parkinson’s, ALS and rapidly progressing multiple sclerosis. The center's strategy is to harness the power of revolutions in the science of complex systems biology and big data to discover why the aging brain is vulnerable to these diseases and to translate these discoveries into precision medicine.


Role of the Keap1/Nrf2 pathway in neurodegenerative diseases

Correspondence: Ken Itoh, MD, PhD, Department of Stress Response Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. Email: [email protected] Search for more papers by this author

Department of Stress Response Science, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

Department of Stress Response Science, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

Department of Stress Response Science, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

Correspondence: Ken Itoh, MD, PhD, Department of Stress Response Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. Email: [email protected] Search for more papers by this author

Abstract

As the elderly population increases, a growing number of individuals suffer from age-associated neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Oxidative stress is considered to play a crucial role in the pathogenesis of age-related diseases. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is activated by oxidative stress and regulates the expression of a variety of antioxidant enzymes and proteins that exert cytoprotective effects against oxidative stress. Numerous studies have addressed the role of Nrf2 in age-related diseases, including neurodegenerative diseases, using animal or in vitro cell culture models. Here, we introduce the role of oxidative stress in the pathogenesis of neurodegenerative diseases and critically examine the recent findings concerning the role for Nrf2 in the amelioration of AD and PD. Nrf2 not only regulates antioxidant proteins but also regulates the genes associated with autophagy and nerve growth factor signaling. Current research unequivocally demonstrates that the activation of the Nrf2 pathway is a promising novel strategy for the prevention and modification of neurodegenerative diseases.


Global Summit on Neurodegenerative Diseases: Biology & Therapeutics

The Global Summit on Neurodegenerative Diseases: Biology & Therapeutics is dedicated to new Insights in Molecular Mechanism and Treatment of Neurodegenerative Diseases.

The Global Summit on Neurodegenerative Diseases: Biology & Therapeutics covers topics such as:

  • CNS and Brain Disorders
  • Neurobiology
  • Parkinson`s Disease
  • Alzheimer`s Disease
  • Neuropathology
  • Huntington`s Disease
  • Epilepsy
  • Neuroimaging
  • Neuroinfections and Neuroimmunology
  • Neurotrauma
  • Natural Products for Neurodegenerative Disease
  • Molecular and Cellular Basis of Neurodegenerative Disease
  • Neurosurgery
  • Neuromuscular Disorders
  • Nanotechnology for Neurodegenerative Disorders
  • Neurogenetic and Neurometabolic Disorders
  • Diagnostics and Case Studies
  • Neurotherapeutics

The Global Summit on Neurodegenerative Diseases: Biology & Therapeutics brings together:


Parkinson’s Disease

Like Alzheimer’s disease, Parkinson’s disease is a neurodegenerative disease. It was first characterized by James Parkinson in 1817. Each year, 50,000-60,000 people in the United States are diagnosed with the disease. Parkinson’s disease causes the loss of dopamine neurons in the substantia nigra, a midbrain structure that regulates movement. Loss of these neurons causes many symptoms including tremor (shaking of fingers or a limb), slowed movement, speech changes, balance and posture problems, and rigid muscles. The combination of these symptoms often causes a characteristic slow hunched shuffling walk, illustrated in Figure 2. Patients with Parkinson’s disease can also exhibit psychological symptoms, such as dementia or emotional problems.

Figure 2. Parkinson’s patients often have a characteristic hunched walk.

Although some patients have a form of the disease known to be caused by a single mutation, for most patients the exact causes of Parkinson’s disease remain unknown: the disease likely results from a combination of genetic and environmental factors (similar to Alzheimer’s disease). Post-mortem analysis of brains from Parkinson’s patients shows the presence of Lewy bodies—abnormal protein clumps—in dopaminergic neurons. The prevalence of these Lewy bodies often correlates with the severity of the disease.

There is no cure for Parkinson’s disease, and treatment is focused on easing symptoms. One of the most commonly prescribed drugs for Parkinson’s is L-DOPA, which is a chemical that is converted into dopamine by neurons in the brain. This conversion increases the overall level of dopamine neurotransmission and can help compensate for the loss of dopaminergic neurons in the substantia nigra. Other drugs work by inhibiting the enzyme that breaks down dopamine.



Comments:

  1. Kordale

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  2. Clust

    It is the precious phrase

  3. Bryceton

    Thanks for the explanation.

  4. Broderik

    Let's live.

  5. Bara

    the Shining idea



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