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      Conventional protein kinase C in the brain: repurposing cancer drugs for neurodegenerative treatment?

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          Abstract

          Protein Kinase C (PKC) isozymes are tightly regulated kinases that transduce a myriad of signals from receptor-mediated hydrolysis of membrane phospholipids. They play an important role in brain physiology, and dysregulation of PKC activity is associated with neurodegeneration. Gain-of-function mutations in PKCα are associated with Alzheimer’s disease (AD) and mutations in PKCγ cause spinocerebellar ataxia (SCA) type 14 (SCA14). This article presents an overview of the role of the conventional PKCα and PKCγ in neurodegeneration and proposes repurposing PKC inhibitors, which failed in clinical trials for cancer, for the treatment of neurodegenerative diseases.

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          Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

          Justin M. Long, David Holtzman (2019)
          Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular amyloid-β deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remain the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease modifying treatment currently exists and numerous phase 3 clinical trials have failed to demonstrate benefit. We review here recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease modifying therapies.
          Article 0 comments Cited 990 times – based on 0 reviews     Review now
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            Variant of TREM2 associated with the risk of Alzheimer's disease.

            Thorlakur Jonsson, Hreinn Stefansson, Stacy Steinberg … (2013)
            Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.).
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              Synergy between amyloid-β and tau in Alzheimer’s disease

              Marc Busche, Bradley T. Hyman (2020)
              Patients with Alzheimer's disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this 'triggering' function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ-tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.
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                Author and article information

                Contributors
                Alexandra C. Newton:
                ORCID: http://orcid.org/0000-0002-2906-3705
                Journal
                Journal ID (nlm-ta): Neuronal Signal
                Journal ID (iso-abbrev): Neuronal Signal
                Journal ID (publisher-id): ns
                Title: Neuronal Signaling
                Publisher: Portland Press Ltd.
                ISSN (Electronic): 2059-6553
                Publication date Collection: December 2021
                Publication date (Electronic): 08 October 2021
                Volume: 5
                Issue: 4
                Electronic Location Identifier: NS20210036
                Affiliations
                Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, U.S.A.
                Author notes
                Correspondence: Alexandra C. Newton ( anewton@ 123456health.ucsd.edu )
                Author information
                http://orcid.org/0000-0002-2906-3705
                Article
                Publisher ID: NS20210036
                DOI: 10.1042/NS20210036
                PMC ID: 8536831
                PubMed ID: 34737895
                SO-VID: ef36496e-4880-46a2-ad28-670963420ea9
                Copyright © © 2021 The Author(s).
                License:

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                Date received : 10 July 2021
                Date revision received : 16 September 2021
                Date accepted : 17 September 2021
                Date: 20 September 2021
                Page count
                Pages: 10
                Categories
                Subject: Neuroscience
                Subject: Signaling
                Subject: Aging
                Subject: Molecular Bases of Health & Disease
                Subject: Review Articles

                Keywords: alzheimer's disease,enzyme mutation,neurodegeneration,protein kinase c,signal transduction,spinocerebellar ataxia
                Data availability:
                Keywords: alzheimer's disease, enzyme mutation, neurodegeneration, protein kinase c, signal transduction, spinocerebellar ataxia

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