Role of Neurotrophic Factor Alterations in the Neurodegenerative Process in HIV Associated Neurocognitive Disorders

Abstract

Migration of HIV infected cells into the CNS is associated with a spectrum of neurological disorders, ranging from milder forms of HIV-associated neurocognitive disorders (HAND) to HIV-associated dementia (HAD). These neuro-psychiatric syndromes are related to the neurodegenerative pathology triggered by the release of HIV proteins and cytokine/chemokines from monocytes/macrophages into the CNS –a condition known as HIV encephalitis (HIVE). As a result of more effective combined anti-retroviral therapy (cART) patients with HIV are living longer and thus the frequency of HAND has increased considerably, resulting in an overlap between the neurodegenerative pathology associated with HIV and that related to aging. In fact, HIV infection is believed to hasten the aging process. The mechanisms through which HIV and aging lead to neurodegeneration include: abnormal calcium flux, excitotoxicity, signaling abnormalities, oxidative stress and autophagy defects. Moreover, recent studies have shown that defects in the processing and transport of neurotrophic factors such as fibroblast growth factors (FGFs), neural growth factor (NGF) and brain-derived growth factor (BDNF) might also play a role. Recent evidence implicates alterations in neurotrophins in the pathogenesis of neurodegeneration associated with HAND in the context of aging. Here, we report FGF overexpression curtails gp120-induced neurotoxicity in a double transgenic mouse model. Furthermore, our data show disparities in brain neurotrophic factor levels may be exacerbated in HIV patients over 50 years of age. In this review, we discuss the most recent findings on neurotrophins and HAND in the context of developing new therapies to combat HIV infection in the aging population.

Growth Factor Signaling: Implications for Disease & Therapeutics

“…This review highlights the key role of targeting FGF2/FGFR1 axis as a therapeutic intervention for CNS diseases (aging and HAND), with the goal of promoting neurogenesis, restoring synaptic plasticity and modulating neuron-glial interactions and inflammation. A comprehensive review by Fields et.al further corroborates the role of FGF1 and FGF2 in neuroprotection against toxicity mediated by HIV proteins in both cell culture and rodent models (Fields et al, 2014). These authors have elegantly discussed how aging and HIV interact to affect various neurotrophins via different mechanisms.…”

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease

“…T helper cells (Th1 and Th2) secrete MMP9 [45], which plays a critical role in the migration of T cells from the blood stream to the brain and other tissues [46, 47]. Additionally, recent advances in neuro-inflammation implicate abnormal neurotrophic factor signaling, including fibroblast growth factors (FGFs) in HIV-associated neurocognitive decline (HAND) [48] and stroke [49]. The increase in CNS FGF levels after resveratrol treatment suggests an effect on growth factors, which may play a role in neuro-resilience in aging and AD.…”

Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats

“…Recent studies have indicated impaired processing and transport of neurotrophic factors in HIV-1 neuropathogenesis [81-83]. The PI3K-mTOR signaling pathway is involved in synaptic plasticity [84-86] and was shown to be dysregulated in the frontal cortex of patients with neuroAIDS [43].…”