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      Primary cilia and ciliary signaling pathways in aging and age-related brain disorders

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          Abstract

          Brain disorders are characterized by the progressive loss of structure and function of the brain as a consequence of progressive degeneration and/or death of nerve cells. Aging is a major risk factor for brain disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. Various cellular and molecular events have been shown to play a role in the progress of neurodegenerative diseases. Emerging studies suggest that primary cilia could be a key regulator in brain diseases. The primary cilium is a singular cellular organelle expressed on the surface of many cell types, such as astrocytes and neurons in the mature brain. Primary cilia detect extracellular cues, such as Sonic Hedgehog (SHH) protein, and transduce these signals into cells to regulate various signaling pathways. Abnormalities in ciliary length and frequency (ratio of ciliated cells) have been implicated in various human diseases, including brain disorders. This review summarizes current findings and thoughts on the role of primary cilia and ciliary signaling pathways in aging and age-related brain disorders.

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          The Hallmarks of Aging

          Carlos López-Otín, Maria Blasco, Linda Partridge … (2014)
          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Alzheimer's disease.

            Philip Scheltens, Kaj Blennow, Monique Breteler … (2016)
            Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research.
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              Patched1 regulates hedgehog signaling at the primary cilium.

              Rajat Rohatgi, Ljiljana Milenkovic, Matthew P. Scott (2007)
              Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9500169
                Journal ID (pubmed-jr-id): 20475
                Journal ID (nlm-ta): Neurobiol Dis
                Journal ID (iso-abbrev): Neurobiol Dis
                Title: Neurobiology of disease
                ISSN (Print): 0969-9961
                ISSN (Electronic): 1095-953X
                Publication date Nihms-submitted: 2 July 2022
                Publication date (Print): February 2022
                Publication date (Electronic): 31 December 2021
                Publication date PMC-release: 14 July 2022
                Volume: 163
                Page: 105607
                Affiliations
                [a ]Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA
                [b ]Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
                [c ]Department of Anatomy, Physiology and Pharmacology, School of Veterinary Medicine, St. George’s University, Grenada
                [d ]Department of Computer Science, College of Engineering, Shantou University, Shantou, Guangdong 515063, China
                [e ]Key Laboratory of Intelligent Manufacturing Technology, Ministry of Education, Shantou University, Shantou, Guangdong 515063, China
                Author notes

                Author contributions

                Conceptualization: R.M. and G.H; writing (original draft preparation): R.M., N.K., and G.H; writing (review and editing): R.M., N.K., L.C., D.M., and G.H. All authors have read and agreed to the published version of the manuscript.

                [* ]Corresponding author at: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880, USA. guoku.hu@ 123456unmc.edu (G. Hu).
                Article
                Manuscript ID: NIHMS1820255
                DOI: 10.1016/j.nbd.2021.105607
                PMC ID: 9280856
                PubMed ID: 34979259
                SO-VID: 3af750d6-0cd9-43bf-9b45-1aa0a9ce0150
                License:

                This is an open access article under the CC BY-NC-ND license( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Subject: Article

                ScienceOpen disciplines: Neurosciences
                Keywords: aging,alzheimer’s disease,parkinson’s disease,amyotrophic lateral sclerosis,primary cilia,hedgehog signaling,wnt signaling,notch signaling
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: aging, alzheimer’s disease, parkinson’s disease, amyotrophic lateral sclerosis, primary cilia, hedgehog signaling, wnt signaling, notch signaling

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