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      Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease

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          Abstract

          Alzheimer’s disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-β (Aβ) accumulation in the brain. Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA, the gene that encodes protein kinase Cα (PKCα), in five of the families. All three variants linked with LOAD displayed increased catalytic activity relative to wild-type PKCα as assessed in live-cell imaging experiments using a genetically encoded PKC activity reporter. Deleting PRKCA in mice or adding PKC antagonists to mouse hippocampal slices infected with a virus expressing the Aβ precursor CT100 revealed that PKCα was required for the reduced synaptic activity caused by Aβ. In PRKCA −/− neurons expressing CT100, introduction of PKCα, but not PKCα lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKCα to the synapse is required for its mediation of the effects of Aβ. Thus, enhanced PKCα activity may contribute to AD, possibly by mediating the actions of Aβ on synapses. In contrast, reduced PKCα activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme.

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          Most cited references36

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          APP processing and synaptic function.

          A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.
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            AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.

            Beta amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Abeta employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Abeta-induced modification of synaptic structure and function.
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              Protein kinase C, an elusive therapeutic target?

              Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumour promoter phorbol ester in 1982. Although initial therapeutic efforts focused on cancer, additional indications--including diabetic complications, heart failure, myocardial infarction, pain and bipolar disorder--were targeted as researchers developed a better understanding of the roles of eight conventional and novel PKC isozymes in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This Review provides a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.
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                Author and article information

                Journal
                101465400
                34171
                Sci Signal
                Sci Signal
                Science signaling
                1945-0877
                1937-9145
                8 December 2016
                10 May 2016
                10 May 2016
                13 December 2016
                : 9
                : 427
                : ra47
                Affiliations
                [1 ]Department of Neurosciences and Division of Biology, Section of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA
                [2 ]Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
                [3 ]Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA
                [4 ]Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
                [5 ]Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA
                [6 ]Biotechnology Centre of Oslo, University of Oslo, Oslo 0317, Norway
                Author notes
                []Corresponding author. anewton@ 123456ucsd.edu (A.C.N.); tanzi@ 123456helix.mgh.harvard.edu (R.E.T.); rmalinow@ 123456ucsd.edu (R.M.)
                [*]

                These authors contributed equally to this work.

                [†]

                Present address: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037, USA.

                Article
                PMC5154619 PMC5154619 5154619 nihpa831834
                10.1126/scisignal.aaf6209
                5154619
                27165780
                40b1d564-cb6c-4199-b89c-46d8497d662b
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