In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ͉ neurodegeneration P arkinson's disease (PD) is a neurodegenerative disorder characterized by disabling motor abnormalities, including tremor, muscle rigidity, paucity of voluntary movements, and postural instability (1). In several mammalian species, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces most of the biochemical and pathological alterations seen in PD, including the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) (1). Current treatment strategies for PD consist primarily of dopamine replacement therapy with levodopa or dopamine agonists (1). Although effective in the early stages of the disease, chronic dopamine replacement therapy can cause debilitating side effects. Accordingly, concerted research efforts have been focused on developing neuroprotective strategies that will halt or slow the progression of PD.Recent evidence implicates cyclin-dependent kinases (CDKs) in the pathogenesis of several neurodegenerative disorders. CDKs are serine͞threonine kinases best characterized for their role in cell cycle progression. To be active, CDKs require binding to specific regulatory partners such as cyclins (2). Up-regulation of a variety of cell cycle-related CDKs and͞or cyclins has been reported in a number of in vitro neuronal death paradigms (3-8).The importance of such observations is substantiated by reports that inappropriate activation of cell cycle-related pathways has been correlated with the pathogenesis of stroke (9, 10) and Alzheimer's disease (11). However, the identity and functional requirement of individual CDK members in neurodegeneration remain to be elucidated.In contrast to the mitotic CDKs, cdk5 activity is predominantly, although not exclusively, associated with postmitotic neurons (12). cdk5 activation requires association with its regulatory partner, p35 (13) or p39 (14). The p35͞cdk5 complex is required for proper development of the central nervous system (15, 16), process outgrowth (17), axonal migration (18, 19), cortical lamination (16, 20), cell adhesion (20), axonal transport (21), and synaptic activity (22). Just as with cell cycle-related CDK...

Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.