Corticotropin releasing factor-binding protein (CRF-BP) as a potential new therapeutic target in Alzheimer’s disease and stress disorders

Abstract Alzheimer’s disease is the most common cause of dementia and one of the most complex human neurodegenerative diseases. Numerous studies have demonstrated a critical role of the environment in the pathogenesis and pathophysiology of the disease, where daily life stress plays an important role. A lot of epigenetic studies have led to the conclusion that chronic stress and stress-related disorders play an important part in the onset of neurodegenerative disorders, and an enormous amount of research yielded valuable discoveries but has so far not led to the development of effective treatment strategies for Alzheimer’s disease. Corticotropin-releasing factor (CRF) is one of the major hormones and at the same time a neuropeptide acting in stress response. Deregulation of protein levels of CRF is involved in the pathogenesis of Alzheimer’s disease, but little is known about the precise roles of CRF and its binding protein, CRF-BP, in neurodegenerative diseases. In this review, we summarize the key evidence for and against the involvement of stress-associated modulation of the CRF system in the pathogenesis of Alzheimer’s disease and discuss how recent findings could lead to new potential treatment possibilities in Alzheimer’s disease by using CRF-BP as a therapeutic target.

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Smuggle tau through a secret(ory) pathway

Biochemical Journal ◽

10.1042/bcj20210324 ◽

2021 ◽

Vol 478 (14) ◽

pp. 2921-2925

Author(s):

Hao Xu (徐昊)

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Recent Work ◽

Molecular Mechanisms ◽

Binding Protein ◽

Nerve Cells ◽

Transmembrane Domains ◽

Tau Pathology ◽

Microtubule Binding

Secretion of misfolded tau, a microtubule-binding protein enriched in nerve cells, is linked to the progression of tau pathology. However, the molecular mechanisms underlying tau secretion are poorly understood. Recent work by Lee et al. [Biochemical J. (2021) 478: 1471–1484] demonstrated that the transmembrane domains of syntaxin6 and syntaxin8 could be exploited for tau release, setting a stage for testing a novel hypothesis that has profound implications in tauopathies (e.g. Alzheimer's disease, FTDP-17, and CBD/PSP) and other related neurodegenerative diseases. The present commentary highlights the importance and limitations of the study, and discusses opportunities and directions for future investigations.

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P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21155485 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5485

Author(s):

Ursula A. Germann ◽

John J. Alam

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Therapeutic Target ◽

Kinase Inhibitors ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Therapeutic Effects ◽

P38α Kinase

Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

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Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

Biochemical Society Transactions ◽

10.1042/bst20170501 ◽

2018 ◽

Vol 46 (4) ◽

pp. 891-909 ◽

Cited By ~ 23

Author(s):

Ruby Macdonald ◽

Katy Barnes ◽

Christopher Hastings ◽

Heather Mortiboys

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

Therapeutic Target ◽

Mitochondrial Dynamics ◽

Central Mechanism ◽

Phenotypic Screening ◽

Mitochondrial Abnormalities

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes.

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Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.662242 ◽

2021 ◽

Vol 15 ◽

Author(s):

Xin Zhang ◽

Nadine Alshakhshir ◽

Liqin Zhao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Redox Homeostasis ◽

Critical Role ◽

Glycolytic Flux ◽

Glycolytic Metabolism ◽

Age Related ◽

Brain Resilience

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

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The Structure and Function of α, β and γ-Secretase as Therapeutic Target Enzymes in the Development of Alzheimer’s Disease: A Review

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666191011145941 ◽

2020 ◽

Vol 18 (9) ◽

pp. 657-667 ◽

Cited By ~ 3

Author(s):

Syed S. Ahmad ◽

Shahzad Khan ◽

Mohammad A. Kamal ◽

Umam Wasi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Amyloid Precursor Protein ◽

Therapeutic Target ◽

Critical Role ◽

Precursor Protein ◽

Model Systems ◽

Diagnostic Tools ◽

Homologous Proteins

: Alzheimer's disease is a progressive neurodegenerative disorder that affects the central nervous system. There are several factors that cause AD, like, intracellular hyperphosphorylated Tau tangles, collection of extracellular Amyloid-β42 and generation of reactive oxygen species due to mitochondrial dysfunction. This review analyses the most active target of AD and both types of AD-like early-onset AD and late-onset AD. BACE1 is a β-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer's disease. The presenilin proteins play a critical role in the pathogenesis of Alzheimer malady by intervening the intramembranous cleavage of amyloid precursor protein and the generation of amyloid β. The two homologous proteins PS1 and PS2 speak to the reactant subunits of particular γ-secretase edifices that intercede an assortment of cellular processes. Natural products are common molecular platforms in drug development in AD. Many natural products are being tested in various animal model systems for their role as a potential therapeutic target in AD. Presently, there are a few theories clarifying the early mechanisms of AD pathogenesis. Recently, research advancements in the field of nanotechnology, which utilize macromolecular strategies to make drugs in nanoscale measurements, offer nanotechnology-based diagnostic tools and drug carriers which are highly sensitive for effective drug targeting in the treatment of Alzheimer’s disease.

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The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2013552117 ◽

2020 ◽

Vol 117 (46) ◽

pp. 29133-29143

Author(s):

Amanda K. Engstrom ◽

Alicia C. Walker ◽

Rohitha A. Moudgal ◽

Dexter A. Myrick ◽

Stephanie M. Kyle ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Neurodegenerative Diseases ◽

Therapeutic Target ◽

Cortical Neurons ◽

Histone Demethylase ◽

Direct Mechanism ◽

Promising Therapeutic Target

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our laboratory implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer's disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopathy mouse model to demonstrate that pathological tau can exclude LSD1 from the nucleus in neurons. In addition, we show that reducing LSD1 in these mice is sufficient to highly exacerbate tau-mediated neurodegeneration and tau-induced gene expression changes. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration and counteract tau-induced expression changes. These results suggest that inhibiting LSD1 via sequestration contributes to tau-mediated neurodegeneration. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimer's disease.

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The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis

Aging and Disease ◽

10.14336/ad.2019.0718 ◽

2020 ◽

Vol 11 (3) ◽

pp. 705 ◽

Cited By ~ 3

Author(s):

Seong Gak Jeon ◽

Anji Yoo ◽

Dong Wook Chun ◽

Sang Bum Hong ◽

Hyunju Chung ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Target ◽

Critical Role

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Corticotropin-Releasing Factor (CRF), CRF-Binding Protein (CRF-BP), and CRF/CRF-BP Complex in Alzheimer's Disease and Control Postmortem Human Brain

Journal of Neurochemistry ◽

10.1046/j.1471-4159.1997.68052053.x ◽

2002 ◽

Vol 68 (5) ◽

pp. 2053-2060 ◽

Cited By ~ 33

Author(s):

Dominic P. Behan ◽

On Khongsaly ◽

Michael J. Owens ◽

Hyung D. Chung ◽

Charles B. Nemeroff ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Brain ◽

Binding Protein ◽

Corticotropin Releasing Factor ◽

Postmortem Human Brain ◽

And Control

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The Role of Mitochondria in Alzheimer's disease: Neurodegenerative Disease and Future Therapeutic Options

Neuroscience and Neurological Surgery ◽

10.31579/2578-8868/026 ◽

2018 ◽

Vol 2 (1) ◽

pp. 01-03

Author(s):

Ruth Angale

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Structural Changes ◽

Late Onset ◽

Critical Role ◽

Neuronal Loss ◽

Ache Inhibitors ◽

Age Related ◽

Mitochondrial Oxidative Damage

Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal and clinical studies suggests that mitochondria play a critical role in aging, cancer, diabetes and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Several lines of research suggest that mitochondrial oxidative damage is an important cellular change in most late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and age-related diseases. In addition, epigenetic factors and lifestyle activities may contribute to selective disease susceptibility for each of these diseases. This paper discusses research that has elucidated features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases. This paper also discusses mitochondrial abnormalities and potential mitochondrial therapeutics in AD. Alzheimer's disease (AD) is characterized by neuronal loss and gradual cognitive impairment. AD is the leading cause of dementia worldwide and the incidence is increasing rapidly, with diagnoses expected to triple by the year 2050. Impaired cholinergic transmission is a major role player in the rapid deterioration associated with AD, primarily as a result of increased acetylcholinesterase (AChE) in the AD brain, responsible for reducing the amount of acetylcholine (ACh). Current drug therapies, known as AChE inhibitors (AChEIs), target this heightened level of AChE in an attempt to slow disease progression. AChEIs have only showed success in the treatment of mild to moderate AD symptoms, with the glutamate inhibitor memantine being the most common drug prescribed for the management of severe AD.

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