{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:40:13Z","timestamp":1789155613883,"version":"build-2803163510"},"reference-count":115,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2009,3,11]],"date-time":"2009-03-11T00:00:00Z","timestamp":1236729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cognitive deficits in patients with HIV profoundly affect the quality of life of people living with this disease and have often been linked to the neuro-inflammatory condition known as HIV encephalitis (HIVE). With the advent of more effective anti-retroviral therapies, HIVE has shifted from a sub-acute to a chronic condition. The neurodegenerative process in patients with HIVE is characterized by synaptic and dendritic damage to pyramidal neurons, loss of calbindin-immunoreactive interneurons and myelin loss. The mechanisms leading to neurodegeneration in HIVE might involve a variety of pathways, and several lines of investigation have found that interference with signaling factors mediating neuroprotection might play an important role. These signaling pathways include, among others, the GSK3b, CDK5, ERK, Pyk2, p38 and JNK cascades. Of these, GSK3b has been a primary focus of many previous studies showing that in infected patients, HIV proteins and neurotoxins secreted by immune-activated cells in the brain abnormally activate this pathway, which is otherwise regulated by growth factors such as FGF. Interestingly, modulation of the GSK3b signaling pathway by FGF1 or GSK3b inhibitors (lithium, valproic acid) is protective against HIV neurotoxicity, and several pilot clinical trials have demonstrated cognitive improvements in HIV patients treated with GSK3b inhibitors. In addition to the GSK3b pathway, the CDK5 pathway has recently been implicated as a mediator of neurotoxicity in HIV, and HIV proteins might activate this pathway and subsequently disrupt the diverse processes that CDK5 regulates, including synapse formation and plasticity and neurogenesis. Taken together, the GSK3b and CDK5 signaling pathways are important regulators of neurotoxicity in HIV, and modulation of these factors might have therapeutic potential in the treatment of patients suffering from HIVE. In this context, the subsequent sections will focus on reviewing the involvement of the GSK3b and CDK5 pathways in neurodegeneration in HIV.<\/jats:p>","DOI":"10.3390\/ijms10031045","type":"journal-article","created":{"date-parts":[[2009,3,11]],"date-time":"2009-03-11T16:35:44Z","timestamp":1236789344000},"page":"1045-1063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Molecular Pathology of Neuro-AIDS (CNS-HIV)"],"prefix":"10.3390","volume":"10","author":[{"given":"Leslie","family":"Crews","sequence":"first","affiliation":[{"name":"Department of Pathology, University of California, San Diego \/ 9500 Gilman Dr. La Jolla, CA 92093, U.S.A.;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Patrick","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California, San Diego \/ 9500 Gilman Dr. La Jolla, CA 92093, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian  L.","family":"Achim","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California, San Diego \/ 9500 Gilman Dr. La Jolla, CA 92093, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian  P.","family":"Everall","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California, San Diego \/ 9500 Gilman Dr. La Jolla, CA 92093, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliezer","family":"Masliah","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Diego \/ 9500 Gilman Dr. La Jolla, CA 92093, U.S.A.;"},{"name":"Department of Neurosciences, University of California, San Diego \/ 9500 Gilman Dr. La Jolla, CA 92093, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2009,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nri1527","article-title":"The neuropathogenesis of AIDS","volume":"5","year":"2005","journal-title":"Nat. Rev. Immunol"},{"key":"ref_2","first-page":"S35","article-title":"The neuropathogenesis of the AIDS dementia complex","volume":"11","author":"Gendelman","year":"1997","journal-title":"Aids"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1017\/S1355617700000230","article-title":"The HNRC 500 - neuropsychology of HIV infection at different disease stages","volume":"1","author":"Heaton","year":"1995","journal-title":"J. Int. Neuropsych. Soc"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1212\/01.WNL.0000034175.11956.79","article-title":"Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis","volume":"59","author":"Cherner","year":"2002","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/ana.410360422","article-title":"HIV encephalitis is the pathologic correlate of dementia in AIDS","volume":"36","author":"Wiley","year":"1994","journal-title":"Ann. Neurol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/BF03033819","article-title":"The shifting patterns of HIV encephalitis neuropathology","volume":"8","author":"Everall","year":"2005","journal-title":"Neurotox. Res"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/j.1365-2559.2004.02004.x","article-title":"An update on the neuropathology of HIV in the HAART era","volume":"45","author":"Bell","year":"2004","journal-title":"Histopathology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1093\/jnen\/62.5.429","article-title":"The changing pattern of HIV neuropathology in the HAART era","volume":"62","author":"Gray","year":"2003","journal-title":"J. Neuropathol. Exp. Neurol"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1080\/13550280390194109","article-title":"Human immunodeficiency virus-associated dementia: an evolving disease","volume":"9","author":"McArthur","year":"2003","journal-title":"J. Neurovirol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1080\/13550280290049615","article-title":"HIV-associated cognitive impairment before and after the advent of combination therapy","volume":"8","author":"Sacktor","year":"2002","journal-title":"J. Neurovirol"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1136\/jnnp.69.3.376","article-title":"Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART)","volume":"69","author":"Maschke","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S1286-4579(02)01542-3","article-title":"HIV-1 and the brain: connections between HIV-1-associated dementia, neuropathology and neuroimmunology","volume":"4","author":"Lawrence","year":"2002","journal-title":"Microbes Infect"},{"key":"ref_13","first-page":"358","article-title":"HIV-1-associated dementia: a basic science and clinical perspective","volume":"12","author":"Diesing","year":"2002","journal-title":"AIDS Read"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1750-3639.2003.tb00040.x","article-title":"Detection of HIV-1 DNA in microglia\/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection","volume":"13","author":"Wiley","year":"2003","journal-title":"Brain Pathol"},{"key":"ref_15","first-page":"858","article-title":"The fine structure of acquired immunodeficiency syndrome encephalopathy","volume":"113","author":"Mirra","year":"1989","journal-title":"Arch. Pathol. Lab. Med"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1172\/JCI115024","article-title":"Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains","volume":"87","author":"Pulliam","year":"1991","journal-title":"J. Clin. Invest"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/jlb.56.3.389","article-title":"The neuropathogenesis of HIV-1 infection","volume":"56","author":"Gendelman","year":"1994","journal-title":"J. Leukocyte Biol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1111\/j.1750-3639.2001.tb00401.x","article-title":"Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS","volume":"11","author":"Langford","year":"2001","journal-title":"Brain Pathol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0022-510X(02)00207-1","article-title":"The role of macrophage\/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis","volume":"202","author":"Minagar","year":"2002","journal-title":"J. Neurol Sci"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.molimm.2004.06.018","article-title":"HIV-infection of the central nervous system: the tightrope walk of innate immunity","volume":"42","author":"Speth","year":"2005","journal-title":"Mol. Immunol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1055\/s-2008-1040830","article-title":"Pathobiology of human immunodeficiency virus dementia","volume":"19","author":"Nath","year":"1999","journal-title":"Semin. Neurol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1172\/JCI25444","article-title":"Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor","volume":"115","author":"Bellizzi","year":"2005","journal-title":"J Clin Invest"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S193","DOI":"10.1086\/344528","article-title":"Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia","volume":"186","author":"Nath","year":"2002","journal-title":"J Infect Dis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8212","DOI":"10.1073\/pnas.96.14.8212","article-title":"Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis","volume":"96","author":"Kaul","year":"1999","journal-title":"Proc. Natl. Acad. Sci USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14500","DOI":"10.1073\/pnas.95.24.14500","article-title":"Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity","volume":"95","author":"Meucci","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1097\/00002030-199809000-00009","article-title":"Chemokines and receptors in HIV encephalitis","volume":"12","author":"Sanders","year":"1998","journal-title":"Aids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1126\/science.2148832","article-title":"Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1","volume":"250","author":"Giulian","year":"1990","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1002\/(SICI)1097-4547(19981115)54:4<530::AID-JNR10>3.0.CO;2-1","article-title":"Differential modulation of cell death proteins in human brain cells by tumor necrosis factor \u03b1 and platelet activating factor","volume":"54","author":"Pulliam","year":"1998","journal-title":"J. Neurosci. Res"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0960-5428(06)80257-3","article-title":"Investigation of HIV-infected macrophage neurotoxin production from patients with AIDS dementia","volume":"4","author":"Pulliam","year":"1994","journal-title":"Adv. Neuroimmunol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1080\/753312749","article-title":"Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis","volume":"10","author":"Wang","year":"2004","journal-title":"J Neurovirol"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1080\/753312761","article-title":"Regulation of cell cycle proteins by chemokine receptors: A novel pathway in human immunodeficiency virus neuropathogenesis?","volume":"10","author":"Brandimarti","year":"2004","journal-title":"J Neurovirol"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1097\/00002030-200209060-00003","article-title":"Chemokine receptors in the brain: their role in HIV infection and pathogenesis","volume":"16","author":"Kolson","year":"2002","journal-title":"Aids"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/ana.410380404","article-title":"AIDS dementia comples and HIV-1 brain infection: clinical-virological correlations","volume":"38","author":"Brew","year":"1995","journal-title":"Ann. Neurol"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1002\/ana.410380510","article-title":"Immunocytochemical quantification of human immunodeficiency virus in the brain: correlations with dementia","volume":"38","author":"Glass","year":"1995","journal-title":"Ann. Neurol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1002\/ana.410420504","article-title":"Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain","volume":"42","author":"McArthur","year":"1997","journal-title":"Ann. Neurol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/ana.410420618","article-title":"Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center","volume":"42","author":"Masliah","year":"1997","journal-title":"Ann. Neurol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1097\/00005072-199505000-00008","article-title":"Differential vulnerability of calbindin-immunoreactive neurons in HIV encephalitis","volume":"54","author":"Masliah","year":"1995","journal-title":"J. Neuropathol. Exp. Neurol"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1097\/00002030-200205030-00008","article-title":"Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy","volume":"16","author":"Langford","year":"2002","journal-title":"AIDS"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1097\/01.aids.0000218552.69834.00","article-title":"Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment","volume":"20","author":"Moore","year":"2006","journal-title":"Aids"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/BF03033826","article-title":"HIV-1, chemokines and neurogenesis","volume":"8","author":"Tran","year":"2005","journal-title":"Neurotox. Res"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1086\/422008","article-title":"HIV-1 promotes quiescence in human neural progenitor cells","volume":"190","author":"Krathwohl","year":"2004","journal-title":"J. Infect. Dis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7319","DOI":"10.1128\/JVI.78.14.7319-7328.2004","article-title":"Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells","volume":"78","author":"Lawrence","year":"2004","journal-title":"J. Virol"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1097\/01.aids.0000189854.06194.87","article-title":"Aberrant cortical neurogenesis in a pediatric neuroAIDS model: neurotrophic effects of growth hormone","volume":"19","author":"Antony","year":"2005","journal-title":"Aids"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/(SICI)1097-4695(199808)36:2<249::AID-NEU11>3.0.CO;2-9","article-title":"Multipotent progenitor cells in the adult dentate gyrus","volume":"36","author":"Gage","year":"1998","journal-title":"J. Neurobiol"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nn1707","article-title":"Potential role for adult neurogenesis in the encoding of time in new memories","volume":"9","author":"Aimone","year":"2006","journal-title":"Nat. Neurosci"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/hipo.20157","article-title":"Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways","volume":"16","author":"Olson","year":"2006","journal-title":"Hippocampus"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/j.1460-9568.2005.03875.x","article-title":"New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment","volume":"21","author":"Laroche","year":"2005","journal-title":"Eur. J. Neurosci"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1046\/j.1460-9568.2003.02647.x","article-title":"Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis","volume":"17","author":"Brown","year":"2003","journal-title":"Eur. J. Neurosci"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/nature04108","article-title":"Wnt signalling regulates adult hippocampal neurogenesis","volume":"437","author":"Lie","year":"2005","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e272","DOI":"10.1371\/journal.pbio.0060272","article-title":"Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus","volume":"6","author":"Jessberger","year":"2008","journal-title":"PLoS Biol"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/35073667","article-title":"Pathways to neuronal injury and apoptosis in HIV-associated dementia","volume":"410","author":"Kaul","year":"2001","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1046\/j.1471-4159.2001.00396.x","article-title":"HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity","volume":"78","author":"Haughey","year":"2001","journal-title":"J. Neurochem"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1046\/j.1471-4159.2002.01212.x","article-title":"Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function","volume":"83","author":"Maragos","year":"2002","journal-title":"J. Neurochem"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1212\/01.WNL.0000042048.85204.3D","article-title":"Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants","volume":"60","author":"Turchan","year":"2003","journal-title":"Neurology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1097\/00126334-200210012-00005","article-title":"Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120","volume":"31","author":"Haughey","year":"2002","journal-title":"J Acquir Immune Defic Syndr"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1080\/13550280290100978","article-title":"Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer\u2019s disease","volume":"8","author":"Mattson","year":"2002","journal-title":"J. Neurovirol"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/jcp.21382","article-title":"HIV-1 Tat inhibits NGF-induced Egr-1 transcriptional activity and consequent p35 expression in neural cells","volume":"216","author":"Darbinian","year":"2008","journal-title":"J. Cell. Physiol"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1471-4159.2007.04746.x","article-title":"Activation of cyclin-dependent kinase 5 by calpains contributes to human immunodeficiency virus-induced neurotoxicity","volume":"103","author":"Wang","year":"2007","journal-title":"J. Neurochem"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1111\/j.1460-9568.2006.04813.x","article-title":"Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3\u03b2 to antagonize nuclear factor-kappaB survival pathway in neurons","volume":"23","author":"Sui","year":"2006","journal-title":"Eur. J. Neurosci"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1046\/j.1471-4159.1999.0730578.x","article-title":"HIV-1 Tat-mediated activation of glycogen synthase kinase-3\u03b2 contributes to Tat-mediated neurotoxicity","volume":"73","author":"Maggirwar","year":"1999","journal-title":"J. Neurochem"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/ana.410420605","article-title":"Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis and activate JNK and ERK mitogen-activated protein kinases in human neurons","volume":"42","author":"Lannuzel","year":"1997","journal-title":"Ann. Neurol"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3109\/10623320109063158","article-title":"Activation of endothelial cell mitogen activated protein kinase ERK(l\/2) by extracellular HIV-1 Tat protein","volume":"8","author":"Rusnati","year":"2001","journal-title":"Endothelium"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"32985","DOI":"10.1074\/jbc.M202803200","article-title":"Fibroblast growth factor 1 regulates signaling via the GSK3\u03b2 pathway: implications for neuroprotection","volume":"277","author":"Hashimoto","year":"2002","journal-title":"J. Biol. Chem"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1471-2202-6-8","article-title":"Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120","volume":"6","author":"Langford","year":"2005","journal-title":"BMC Neurosci"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1046\/j.0953-816x.2001.01572.x","article-title":"Activation of glycogen synthase kinase 3 \u03b2 (GSK-3\u03b2) by platelet activating factor mediates migration and cell death in cerebellar granule neurons","volume":"13","author":"Tong","year":"2001","journal-title":"Eur. J. Neurosci"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"11047","DOI":"10.1523\/JNEUROSCI.2733-07.2007","article-title":"Human immunodeficiency virus-1\/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons","volume":"27","author":"Alirezaei","year":"2007","journal-title":"J. Neurosci"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1182\/blood.V98.10.2909","article-title":"HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling","volume":"98","author":"Liu","year":"2001","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1080\/753312758","article-title":"Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis","volume":"10","author":"Yi","year":"2004","journal-title":"J. Neurovirol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1093\/jnen\/60.3.293","article-title":"Amelioration of neurotoxic effects of HIV envelope protein gp120 by fibroblast growth factor: a strategy for neuroprotection","volume":"60","author":"Everall","year":"2001","journal-title":"J. Neuropathol. Exp. Neurol"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/(SICI)1097-4547(20000301)59:5<671::AID-JNR10>3.0.CO;2-B","article-title":"Fibroblast growth factor modulates HIV co-receptor expression by neural cells","volume":"59","author":"Sanders","year":"2000","journal-title":"J. Neurosci. Res"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00441-003-0756-7","article-title":"Fibroblast growth factors and their receptors in the central nervous system","volume":"313","author":"Reuss","year":"2003","journal-title":"Cell. Tissue Res"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.cytogfr.2005.01.004","article-title":"Fibroblast growth factor\/fibroblast growth factor receptor system in angiogenesis","volume":"16","author":"Presta","year":"2005","journal-title":"Cytokine Growth Factor Rev"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1080\/13550280290100996","article-title":"Role of trophic factors on neuroimmunity in neurodegenerative infectious diseases","volume":"8","author":"Langford","year":"2002","journal-title":"J. Neurovirol"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"14063","DOI":"10.1074\/jbc.273.23.14063","article-title":"The activation of glycogen synthase by insulin switches from kinase inhibition to phosphatase activation during adipogenesis in 3T3-L1 cells","volume":"273","author":"Brady","year":"1998","journal-title":"J. Biol. Chem"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1042\/bj3030027","article-title":"The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cells","volume":"303","author":"Saito","year":"1994","journal-title":"Biochem J"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1006\/mcne.2002.1196","article-title":"Lithium ameliorates HIV-gp120-mediated neurotoxicity","volume":"21","author":"Everall","year":"2002","journal-title":"Mol. Cell. Neurosci"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1523\/JNEUROSCI.4321-06.2007","article-title":"Neuroprotective effects of regulators of the glycogen synthase kinase-3\u03b2 signaling pathway in a transgenic model of Alzheimer\u2019s disease are associated with reduced amyloid precursor protein phosphorylation","volume":"27","author":"Rockenstein","year":"2007","journal-title":"J. Neurosci"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11481-006-9051-1","article-title":"Glycogen synthase kinase 3 \u03b2 (GSK-3\u03b2) as a therapeutic target in neuroAIDS","volume":"2","author":"Dewhurst","year":"2007","journal-title":"J. Neuroimmune Pharmacol"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/09540260701877670","article-title":"Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders","volume":"20","author":"Ances","year":"2008","journal-title":"Int. Rev. Psychiatry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1212\/01.wnl.0000204294.28189.03","article-title":"Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report","volume":"66","author":"Schifitto","year":"2006","journal-title":"Neurology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1523\/JNEUROSCI.2164-05.2005","article-title":"Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis","volume":"25","author":"Dou","year":"2005","journal-title":"J. Neurosci"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"9162","DOI":"10.1523\/JNEUROSCI.23-27-09162.2003","article-title":"Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis","volume":"23","author":"Dou","year":"2003","journal-title":"J. Neurosci"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1097\/01.aids.0000244208.49123.1b","article-title":"Lithium improves HIV-associated neurocognitive impairment","volume":"20","author":"Letendre","year":"2006","journal-title":"Aids"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.neuroscience.2005.04.061","article-title":"Implication of cyclin-dependent kinase 5 in the neuroprotective properties of lithium","volume":"134","author":"Jorda","year":"2005","journal-title":"Neuroscience"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.jneuroim.2004.08.026","article-title":"Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis","volume":"157","author":"Masliah","year":"2004","journal-title":"J. Neuroimmunol"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"375","DOI":"10.2174\/1568007033482706","article-title":"Cdk5 in the adult non-demented brain","volume":"2","author":"Fischer","year":"2003","journal-title":"Curr. Drug Targets CNS Neurol. Disord"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.molbrainres.2005.04.014","article-title":"Cyclin-dependent kinase 5 activators p35 and p39 facilitate formation of functional synapses","volume":"138","author":"Johansson","year":"2005","journal-title":"Brain Res. Mol. Brain Res"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"18567","DOI":"10.1073\/pnas.0810137105","article-title":"Cdk5 is essential for adult hippocampal neurogenesis","volume":"105","author":"Lagace","year":"2008","journal-title":"Proc. Natl. Acad. Sci USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S0092-8674(03)00605-6","article-title":"Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration","volume":"114","author":"Xie","year":"2003","journal-title":"Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.neuron.2007.09.035","article-title":"Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK","volume":"56","author":"Samuels","year":"2007","journal-title":"Neuron"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.neuron.2005.10.033","article-title":"Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory","volume":"48","author":"Fischer","year":"2005","journal-title":"Neuron"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4823","DOI":"10.1523\/JNEUROSCI.1331-05.2005","article-title":"Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2","volume":"25","author":"Tang","year":"2005","journal-title":"J. Neurosci"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/35096019","article-title":"A decade of CDK5","volume":"2","author":"Dhavan","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1111\/j.1471-4159.2003.02328.x","article-title":"Cyclin-dependent kinase-5 in neurodegeneration","volume":"88","author":"Shelton","year":"2004","journal-title":"J. Neurochem"},{"key":"ref_95","first-page":"277","article-title":"Cdk5 on the brain","volume":"12","author":"Smith","year":"2001","journal-title":"Cell Growth Differ"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1101\/gad.13.12.1501","article-title":"CDK inhibitors: positive and negative regulators of Gl-phase progression","volume":"13","author":"Sherr","year":"1999","journal-title":"Genes Dev"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1159\/000074624","article-title":"The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator","volume":"12","author":"Hisanaga","year":"2003","journal-title":"Neurosignals"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"6758","DOI":"10.1523\/JNEUROSCI.21-17-06758.2001","article-title":"p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment","volume":"21","author":"Ko","year":"2001","journal-title":"J. Neurosci"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"9658","DOI":"10.1523\/JNEUROSCI.1773-05.2005","article-title":"Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation","volume":"25","author":"Cicero","year":"2005","journal-title":"J. Neurosci"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1111\/j.1471-4159.2005.03301.x","article-title":"Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation","volume":"94","author":"Zhu","year":"2005","journal-title":"J. Neurochem"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"11156","DOI":"10.1073\/pnas.96.20.11156","article-title":"Regulation of cyclin-dependent kinase 5 catalytic activity by phosphorylation","volume":"96","author":"Sharma","year":"1999","journal-title":"Proc. Natl. Acad. Sci USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1159\/000074543","article-title":"Cdk7 functions as a cdk5 activating kinase in brain","volume":"13","author":"Rosales","year":"2003","journal-title":"Cell Physiol Biochem"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1242\/jcs.113.6.1059","article-title":"Brain-derived neurotrophic factor-induced phosphorylation of neurofilament-H subunit in primary cultures of embryo rat cortical neurons","volume":"113","author":"Tokuoka","year":"2000","journal-title":"J Cell Sci"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"9858","DOI":"10.1523\/JNEUROSCI.18-23-09858.1998","article-title":"Evidence for the participation of the neuron-specific CDK5 activator P35 during laminin-enhanced axonal growth","volume":"18","author":"Paglini","year":"1998","journal-title":"J. Neurosci"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0166-2236(00)01663-5","article-title":"Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?","volume":"24","author":"Copani","year":"2001","journal-title":"Trends Neurosci"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/45159","article-title":"Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration","volume":"402","author":"Patrick","year":"1999","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.pharmthera.2005.09.005","article-title":"The cell cycle as a therapeutic target for Alzheimer\u2019s disease","volume":"111","author":"Neve","year":"2006","journal-title":"Pharmacol. Ther"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/35012636","article-title":"Neurotoxicity induces cleavage of p35 to p25 by calpain","volume":"405","author":"Lee","year":"2000","journal-title":"Nature"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1002\/1531-8249(200002)47:2<186::AID-ANA8>3.0.CO;2-3","article-title":"Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine","volume":"47","author":"Nath","year":"2000","journal-title":"Ann. Neurol"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/00126334-200501010-00021","article-title":"Could cholinesterase inhibitors and memantine alleviate HIV dementia?","volume":"38","author":"Alisky","year":"2005","journal-title":"J. Acquir. Immune Defic. Syndr"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"i29","DOI":"10.1136\/jnnp.2003.034348","article-title":"The neurology of HIV infection","volume":"75","author":"Manji","year":"2004","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1093\/jac\/dkf227","article-title":"Cyclin-dependent kinases as cellular targets for antiviral drugs","volume":"50","author":"Schang","year":"2002","journal-title":"J. Antimicrob. Chemother"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"9408","DOI":"10.1200\/JCO.2005.01.5594","article-title":"Targeting the cell cycle: a new approach to cancer therapy","volume":"23","author":"Schwartz","year":"2005","journal-title":"J. Clin. Oncol"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ejps.2005.02.001","article-title":"Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat","volume":"25","author":"Vita","year":"2005","journal-title":"Eur. J. Pharm. Sci"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"8333","DOI":"10.1073\/pnas.0500989102","article-title":"Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury","volume":"102","author":"Movsesyan","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/10\/3\/1045\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:10:01Z","timestamp":1760220601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/10\/3\/1045"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,11]]},"references-count":115,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2009,3]]}},"alternative-id":["i10031045"],"URL":"https:\/\/doi.org\/10.3390\/ijms10031045","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,11]]}}}