In recent years, human immunodeficiency virus (HIV)-infected patients under highly active anti-retroviral therapy (HAART) regimens have shown a markedly improved general clinical status; however, the prevalence of mild cognitive disorders has increased. We propose that increased longevity with HIV-mediated chronic inflammation combined with the secondary effects of HAART may increase the risk of early brain aging as shown by intraneuronal accumulation of abnormal protein aggregates like amyloid β (Aβ), which might participate in worsening the neurodegenerative process and cognitive impairment in older patients with HIV. For this purpose, levels and distribution of Aβ immunoreactivity were analyzed in the frontal cortex of 43 patients with HIV (ages 38-60) and HIV− age-matched controls. Subcellular localization of the Aβ-immunoreactive material was analyzed by double labeling and confocal microscopy and by immunono-electron microscopy (EM). Compared to HIV− cases, in HIV+ cases, there was abundant intracellular Aβ immunostaining in pyramidal neurons and along axonal tracts. Cases with HIV encephalitis (HIVE) had higher levels of intraneuronal Aβ immunoreactivity compared to HIV+ cases with no HIVE. Moreover, levels of intracellular Aβ correlated with age in the group with HIVE. Double-labeling analysis showed that the Aβ-immunoreactive granules in the neurons co-localized with lysosomal markers such as cathepsin-D and LC3. Ultrastructural analysis by immuno-EM has confirmed that in these cases, intracellular Aβ was often found in structures displaying morphology similar to autophagosomes. These findings suggest that long-term survival with HIV might interfere with clearance of proteins such as Aβ and worsen neuronal damage and cognitive impairment in this population.

Objective: We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences.Methods: This was a case-control comparison of HIV-1 seropositive (HIV1) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified as controls, latent HIV CNS infection, and HIV encephalitis (HIVE). Analysis of epigenetic markers including BCL11B, neurodegeneration, and neuroinflammation was performed utilizing immunoblot, confocal microscopy, immunochemistry/image analysis, and qPCR. Detailed antemortem neurocognitive data were available for 23 out of the 32 cases.Results: HIV1 controls (n 5 12) had no detectable HIV-1 DNA, RNA, or p24 in the CNS; latent HIV1 cases (n 5 10) showed high levels of HIV-1 DNA but no HIV RNA or p24; and HIVE cases (n 5 10) had high levels of HIV-1 DNA, RNA, and p24. Compared to HIV1 controls, the HIV1 latent cases displayed moderate cognitive impairment with neurodegenerative and neuroinflammatory alterations, although to a lesser extent than HIVE cases. Remarkably, HIV1 latent cases showed higher levels of BCL11B and other chromatin modifiers involved in silencing. Increased BCL11B was associated with deregulation of proinflammatory genes like interleukin-6, tumor necrosis factor-a, and CD74. Conclusion:Persistence of latent HIV-1 infection in the CNS was associated with increased levels of chromatin modifiers, including BCL11B. Alteration of these epigenetic factors might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment. BCL11B and other epigenetic factors involved in silencing might represent potential targets for HIV-1 involvement of the CNS.

Parkinson disease (PD) is a multifactorial neurodegenerative disorder with high incidence in the elderly, where environmental and genetic factors are involved in etiology. In addition, epigenetic mechanisms, including deregulation of DNA methylation have been recently associated to PD. As accurate diagnosis cannot be achieved pre-mortem, identification of early pathological changes is crucial to enable therapeutic interventions before major neuropathological damage occurs. Here we investigated genome-wide DNA methylation in brain and blood samples from PD patients and observed a distinctive pattern of methylation involving many genes previously associated to PD, therefore supporting the role of epigenetic alterations as a molecular mechanism in neurodegeneration. Importantly, we identified concordant methylation alterations in brain and blood, suggesting that blood might hold promise as a surrogate for brain tissue to detect DNA methylation in PD and as a source for biomarker discovery.

A number of studies suggest an association between Alzheimer's disease (AD) and diabetes: AD patients show impaired insulin function, whereas cognitive deficits and increased risk of developing AD occur in diabetic patients. The reasons for the increased risk are not known. Recent studies of disturbances in the insulin-signaling pathway have revealed new perspectives on the links between AD and Type 1 diabetes with a particular focus on glycogen synthase-kinase-3 (GSK3). We have therefore characterized a mouse model of combined insulin-deficient diabetes and AD and find that diabetes exaggerated defects in the brain of APP transgenic mice. Mice with combined APP overexpression and diabetes showed a decreased insulin receptor activity and an increased GSK3β activity. Concomitantly, tau phosphorylation and number of Aβ plaques, the two pathologic hallmarks of AD, were increased in the brain of diabetic-APP transgenic mice. Our results indicate that the pathologic features of AD are exaggerated in the brain of APP transgenic mice that have concurrent insulin-deficient diabetes, and underscore a possible mechanism of brain dysfunction common to AD and diabetes.

Antiretroviral therapy has increased the life span of HIVϩ individuals; however, HIV-associated neurocognitive disorder (HAND)occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain ␤ II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND.