Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP-binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV-associated neurocognitive disorders (HAND) and in cocaine-mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV-Tat significantly decreases LXRβ levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.

We present a case of a patient with tertiary syphilis, manifesting as acute psychosis, auditory hallucinations and intermittent explosive disorder with pending legal ramifications for physical violence. Our patient had been seen and treated by a psychologist with Aripiprazole for his erratic and aggressive behavior coupled with his new found psychosis over a one-year period with no avail. Prior accounts of interaction with the patient described him as "easy going", "laid back", and cooperative. Our patient had a complete return to baseline mentation and functionality post treatment with 4 Million Units every four hours of penicillin for two weeks. Neurosyphilis is a disease that greatly affects the mental functioning capacity of those infected. While treatment of syphilis has become greatly straightforward, those living in impoverished conditions and without a continual access to the health care system can progress through the stages of syphilis. It is of vital importance to keep syphilis on our differential for patients with rapidly progressing and broadly encompassing psychiatric disturbances especially in patients that have a lower socioeconomic status.

Background: Diseases and disorders with a chronic neuroinflammatory component are often linked with changes in brain metabolism. Among neurodegenerative disorders, people living with human immunodeficiency virus (HIV) and Alzheimer's disease (AD) are particularly vulnerable to metabolic disturbances, but the mechanistic connections of inflammation, neurodegeneration and bioenergetic deficits in the central nervous system (CNS) are poorly defined. The particularly interesting new cysteine histidine-rich-protein (PINCH) is nearly undetectable in healthy mature neurons, but is robustly expressed in tauopathy-associated neurodegenerative diseases including HIV infection and AD. Although robust PINCH expression has been reported in neurons in the brains of patients with HIV and AD, the molecular mechanisms and cellular consequences of increased PINCH expression in CNS disease remain largely unknown. Methods: We investigated the regulatory mechanisms responsible for PINCH protein-mediated changes in bioenergetics, mitochondrial subcellular localization and bioenergetic deficits in neurons exposed to physiological levels of TNFα or the HIV protein Tat. Changes in the PINCH-ILK-Parvin (PIP) complex association with cofilin and TESK1 were assessed to identify factors responsible for actin depolymerization and mitochondrial mislocalization. Lentiviral and pharmacological inhibition experiments were conducted to confirm PINCH specificity and to reinstate proper proteinprotein complex communication. Results: We identified MEF2A as the PINCH transcription factor in neuroinflammation and determined the biological consequences of increased PINCH in neurons. TNFα-mediated activation of MEF2A via increased cellular calcium induced PINCH, leading to disruption of the PIP ternary complex, cofilin activation by TESK1 inactivation, and actin depolymerization. The disruption of actin led to perinuclear mislocalization of mitochondria by destabilizing the kinesindependent mitochondrial transport machinery, resulting in impaired neuronal metabolism. Blocking TNFα-induced PINC H expression preserved mitochondrial localization and maintained metabolic functioning.

Diseases and disorders with a chronic neuroinflammatory component are often linked with changes in brain metabolism. Among neurodegenerative disorders, people living with human immunodeficiency virus (HIV) and Alzheimer’s disease (AD) are particularly vulnerable to metabolic disturbances, but mechanistic connections of inflammation, neurodegeneration and bioenergetic deficits in the central nervous system (CNS) are poorly defined. The particularly interesting new cystine histidine-rich protein called PINCH is nearly undetectable in healthy mature neurons, but is robustly expressed in tauopathy-associated neurodegenerative diseases including HIV infection and AD. Although robust PINCH expression has been reported in neurons in the brains of patients with HIV and AD, the molecular mechanisms and cellular consequences of increased PINCH expression in CNS disease was not known. In this context, we have identified the transcription factor responsible for PINCH induction in neuroinflammatory conditions and the effects of increased PINCH expression in neurons. Given that AD and neuroHIV share pathological features including cognitive impairment with chronic neuroinflammation, TNFa plays an important role in neurodegenerative processes. The viral protein Tat, is produced in the brain and is one of the main drivers of neuroinflammation and strongly induces TNFa. Our data show that TNFα-mediated activation of MEF2A via increased cellular calcium induces PINCH. In turn, this leads to disruption of the PINCH-ILK-Parvin ternary complex, cofilin activation by Tesk1 inactivation, and actin depolymerization. Disruption of actin led to perinuclear mislocalization of mitochondria by destabilizing the kinesin-dependent mitochondrial transport machinery resulting in impaired neuronal metabolism. Blocking TNFα-induced PINCH preserves mitochondrial localization and maintains metabolic functioning. These data report for the first time mechanistic and biological consequences of PINCH expression in neurons in the CNS in diseases with a chronic neuroinflammatory component. These findings point to maintenance of PINCH at normal physiological levels as a new therapeutic target for neurodegenerative diseases with impaired metabolism.

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