Increased CDK5 Expression in HIV Encephalitis Contributes to Neurodegeneration via Tau Phosphorylation and Is Reversed with Roscovitine

Abstract

Recent treatments with highly active antiretroviral therapy (HAART) regimens have been shown to improve general clinical status in patients with human immunodeficiency virus (HIV) infection; however, the prevalence of cognitive alterations and neurodegeneration has remained the same or has increased. These deficits are more pronounced in the subset of HIV patients with the inflammatory condition known as HIV encephalitis (HIVE). Activation of signaling pathways such as GSK3␤ and CDK5 has been implicated in the mechanisms of HIV neurotoxicity; however, the downstream mediators of these effects are unclear. The present study investigated the involvement of CDK5 and tau phosphorylation in the mechanisms of neurodegeneration in HIVE. In the frontal cortex of patients with HIVE, increased levels of CDK5 and p35 expression were associated with abnormal tau phosphorylation. Similarly, transgenic mice engineered to express the HIV protein gp120 exhibited increased brain levels of CDK5 and p35, alterations in tau phosphorylation, and dendritic degeneration. In contrast, genetic knockdown of CDK5 or treatment with the CDK5 inhibitor roscovitine improved behavioral performance in the water maze test and reduced neurodegeneration, abnormal tau phosphorylation, and astrogliosis in gp120 transgenic mice. These findings indicate that abnormal CDK5 activation contributes to the neurodegenerative process in HIVE via abnormal tau phosphorylation; thus, reducing CDK5 might ameliorate the cognitive impairments associated with HIVE. The human immunodeficiency virus (HIV) enters the central nervous system (CNS) early in the progression of the disease, resulting in a spectrum of behavioral and motor alterations that range from mild cognitive deficits to dementia.

Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

“…Chronic HIV and simian immunodeficiency virus [SIV] infection also dysregulate the vascular endothelial growth factor [VEGF] [74], RTKs recepteur d'orgine nantais [73], and platelet-derived growth factor [PDGF] signaling [75]. In addition to these signaling pathways, recent studies have shown that CDK5 is hyper-activated [67, 76, 77] in patients with HAND. Therefore, among other pathways through which Tat might lead to neurodegeneration is by aberrant activation of signaling pathways such as CDK5, which is an important pathway for cell survival.…”

“…Recent work indicates that CDK5 might also be involved in the mechanisms of neurotoxicity in patients with HAND [67, 76, 77]. For example, a previous gene array study showed that expression levels of CDK5 and related family members are abnormally expressed in patients with HIVE [94].…”

Molecular and pathologic insights from latent HIV-1 infection in the human brain

“…Total protein homogenates were prepared from flash-frozen postmortem frontal cortex samples as described. 13 HIV-1 p24 was quantified by ELISA (PerkinElmer, Waltham, MA) on homogenate aliquots containing 20 mg of total protein. Real-time PCR analysis of gene expression.…”

S-nitrosylation of Cdk5

“…Furthermore, dysregulation of Cdk5 activity may play a role not only in AD but also in several other neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson disease, Huntington disease and HIV-associated neurocognitive disorders. 7,11,59,60 Thus, our finding that SNO-Cdk5 mediates neuronal injury may be important not only in AD but also in these other neurological diseases. Moreover, this SNO-Cdk5 its kinase activity, (3) as a negative feedback mechanism, SNO-Cdk5 phosphorylates and inhibits NOS1, (4) SNO-Cdk5 hyperactivates the mitochondrial fission protein Drp1 via transnitrosylation, and (5) excessive mitochondrial fission results in bioenergetic failure and synaptic loss in AD (Fig.…”

“…[4][5][6] Dysregulation of Cdk5 activity has been implicated in stroke and many neurodegenerative disorders, including Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, Huntington disease and HIV-associated neurocognitive disorders. [7][8][9][10][11][12][13] Under these neurodegenerative conditions, neurotoxic stimuli such as oxidative stress, mitochondrial dysfunction, excitotoxicity, amyloid-β (Aβ) exposure, calcium overload, and neuroinflammation trigger the hyperactivation of Cdk5 via the calciumdependent protease calpain, which cleaves the Cdk5 activator p35 (or p39) into p25 (or p29). [14][15][16][17][18] Thus, the accumulation of p25, due to the conversion of p35 to p25 (or p39 to p29), activates various events associated with neurodegeneration.…”