Altered nociception in Alzheimer's disease is associated with STEP signaling.

ABSTRACT Alzheimer's disease (AD) is the most common form of dementia, accounting for approximately 60% of cases. In addition to memory loss, changes in pain sensitivity are found in a substantial proportion of AD patients. However, the mechanism of nociception deficits in AD is still unclear. Here, we hypothesize that the nociception abnormality in AD is due to the aberrant activation of striatal-enriched protein tyrosine phosphatase (STEP) signaling, which modulates proteins related to nociception transduction. Our results indicated that the transgenic mice carrying human amyloid precursor protein (APP) gene had lower sensitivity to mechanical and thermal stimulation than the WT group at the ages of 6, 9, and 12 months. These APP mice exhibited elevated STEP activity and decreased phosphorylation of proteins involved in nociception transduction in hippocampi. The pharmacological inhibition of STEP activity using TC-2153 further reversed nociception and cognitive deficits in the APP mice. Moreover, the phosphorylation of nociception-related proteins in the APP mice was also rescued after STEP inhibitor treatment, indicating the key role of STEP in nociception alteration. In summary, this study identifies a mechanism for the reduced nociceptive sensitivity in an AD mouse model that could serve as a therapeutic target to improve the quality of life for AD patients.

[1]  Julie A. Harris,et al.  Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease , 2018, bioRxiv.

[2]  K. Wieczorowska-Tobis,et al.  Pain as a challenge in nursing home residents with behavioral and psychological symptoms of dementia , 2018, Clinical interventions in aging.

[3]  M. Geschwind,et al.  Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. , 2018, Cold Spring Harbor perspectives in biology.

[4]  G. Sergi,et al.  Is pain sensitivity altered in people with Alzheimer's disease? A systematic review and meta-analysis of experimental pain research , 2016, Experimental Gerontology.

[5]  C. Ballard,et al.  Reduced thermal sensitivity and increased opioidergic tone in the TASTPM mouse model of Alzheimer's disease , 2016, Pain.

[6]  P. Lombroso,et al.  Striatal-enriched protein tyrosine phosphatase modulates nociception: evidence from genetic deletion and pharmacological inhibition , 2016, Pain.

[7]  Phillip D. Fletcher,et al.  Pain and temperature processing in dementia: a clinical and neuroanatomical analysis , 2015, Brain : a journal of neurology.

[8]  Marina de Tommaso,et al.  Experimental pain processing in individuals with cognitive impairment: current state of the science , 2015, Pain.

[9]  Lei Shi,et al.  GABAergic Inhibition Regulated Pain Sensitization through STEP61 Signaling in Spinal Dorsal Horn of Mice , 2015, Anesthesiology.

[10]  Nicola White,et al.  Pain, agitation, and behavioural problems in people with dementia admitted to general hospital wards: a longitudinal cohort study , 2015, Pain.

[11]  P. Greengard,et al.  Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease , 2014, PLoS biology.

[12]  D. Aarsland,et al.  The response of agitated behavior to pain management in persons with dementia. , 2014, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[13]  Michel Boulouard,et al.  Object recognition test in mice , 2013, Nature Protocols.

[14]  M. Lapeyre-Mestre,et al.  Potential underuse of analgesics for recognized pain in nursing home residents with dementia: A cross-sectional study , 2013, PAIN®.

[15]  S. McMahon,et al.  Perturbing PSD-95 Interactions With NR2B-subtype Receptors Attenuates Spinal Nociceptive Plasticity and Neuropathic Pain , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  P. Greengard,et al.  Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer’s disease mouse model , 2010, Proceedings of the National Academy of Sciences.

[17]  R. Dingledine,et al.  Glutamate Receptor Ion Channels: Structure, Regulation, and Function , 2010, Pharmacological Reviews.

[18]  Paul Greengard,et al.  Aβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61 , 2010, The Journal of Neuroscience.

[19]  C. Fairbanks,et al.  Disruption of nNOS‐PSD95 protein–protein interaction inhibits acute thermal hyperalgesia and chronic mechanical allodynia in rodents , 2009, British journal of pharmacology.

[20]  J. Bibb,et al.  Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-Mediated Cleavage of STEP , 2009, The Journal of Neuroscience.

[21]  K. Davies,et al.  Phospho-regulation of synaptic and extrasynaptic N-methyl-d-aspartate receptors in adult hippocampal slices , 2009, Neuroscience.

[22]  L. Menescal-de-Oliveira,et al.  Role of cholinergic, opioidergic and GABAergic neurotransmission of the dorsal hippocampus in the modulation of nociception in guinea pigs. , 2008, Life sciences.

[23]  F. Guimarães,et al.  Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders. , 2008, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[24]  V. Bubeníková-Valešová,et al.  Different transfer of nociceptive sensitivity from rats with postnatal hippocampal lesions to control rats , 2007, The European journal of neuroscience.

[25]  A. Kazemnejad,et al.  Antinociceptive effect of intra-hippocampal CA1 and dentate gyrus injection of MK801 and AP5 in the formalin test in adult male rats. , 2007, European journal of pharmacology.

[26]  K. Nikolich,et al.  Regulation of NMDA receptor trafficking and function by striatal‐enriched tyrosine phosphatase (STEP) , 2006, The European journal of neuroscience.

[27]  N. Naghdi,et al.  Microinjection of ritanserin into the dorsal hippocampal CA1 and dentate gyrus decrease nociceptive behavior in adult male rat , 2006, Behavioural Brain Research.

[28]  L. Mucke,et al.  Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[29]  H. Suh,et al.  Involvement of phosphorylated extracellular signal-regulated kinase in the mouse substance P pain model. , 2005, Brain research. Molecular brain research.

[30]  S. Jabbur,et al.  Effects of ventral hippocampal lesion on thermal and mechanical nociception in neonates and adult rats , 2004, The European journal of neuroscience.

[31]  Fengli Jiang,et al.  Nociception-driven decreased induction of Fos protein in ventral hippocampus field CA1 of the rat , 2004, Brain Research.

[32]  R. Huganir,et al.  MAPK cascade signalling and synaptic plasticity , 2004, Nature Reviews Neuroscience.

[33]  F. Cerveró,et al.  Extracellular signaling-regulated kinase-1 and -2 (ERK 1/2) mediate referred hyperalgesia in a murine model of visceral pain. , 2003, Brain research. Molecular brain research.

[34]  R. Pulido,et al.  Differential interaction of the tyrosine phosphatases PTP-SL, STEP and HePTP with the mitogen-activated protein kinases ERK1/2 and p38alpha is determined by a kinase specificity sequence and influenced by reducing agents. , 2003, The Biochemical journal.

[35]  R. Melzack,et al.  Blocking NMDA Receptors in the Hippocampal Dentate Gyrus with AP5 Produces Analgesia in the Formalin Pain Test , 2001, Experimental Neurology.

[36]  E. Shimizu,et al.  NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. , 2000, Science.

[37]  F. Benedetti,et al.  Autonomic responses and pain perception in Alzheimer’s disease , 2000, European journal of pain.

[38]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[39]  A I Basbaum,et al.  Impaired nociception and pain sensation in mice lacking the capsaicin receptor. , 2000, Science.

[40]  W. Lim,et al.  PSD-95 Assembles a Ternary Complex with theN-Methyl-d-aspartic Acid Receptor and a Bivalent Neuronal NO Synthase PDZ Domain* , 1999, The Journal of Biological Chemistry.

[41]  J. Macdonald,et al.  Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. , 1999, Science.

[42]  F. Benedetti,et al.  Pain threshold and tolerance in Alzheimer's disease , 1999, Pain.

[43]  P. Lombroso,et al.  Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[44]  P. Sandroni,et al.  International association for the study of pain , 1986, Pain.

[45]  X. Gu,et al.  Tyrosine phosphorylation of the N-Methyl-D-Aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine , 2009, Molecular pain.

[46]  阿部 哲也.  Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain , 2006 .

[47]  P. Greengard,et al.  Regulation of NMDA receptor trafficking by amyloid-beta. , 2005, Nature neuroscience.

[48]  P. Tan,et al.  Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat , 2005, Gene Therapy.

[49]  Angus C. Nairn,et al.  NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling , 2003, Nature Neuroscience.

[50]  E. Scherder,et al.  Alzheimer patients report less pain intensity and pain affect than non-demented elderly. , 1999, Psychiatry.