Protecting the Synapse: Evidence for a Rational Strategy to Treat HIV-1 Associated Neurologic Disease

Abstract

Loss of synaptic integrity and function appears to underlie neurologic deficits in patients with HIV-1-associated dementia (HAD) and other chronic neurodegenerative diseases. Because synaptic injury often long precedes neuronal death and surviving neurons possess a remarkable capacity for synaptic repair and functional recovery, we hypothesize that therapeutic intervention to protect synapses has great potential to improve neurologic function in HAD and other diseases. We discuss findings from both HAD and Alzheimer's disease to demonstrate that the disruption of synaptic structure and function that can occur during excitotoxic injury and neuroinflammation represents a likely substrate for neurologic deficits. Based on available evidence, we provide a rationale for future studies aimed at identifying molecular targets for synaptic protection in neurodegenerative disease. Whereas patients with HAD beginning antiretroviral therapy have shown reversal of neurologic symptoms that is unique for patients with chronic neurodegenerative conditions, we propose that the potential for such reversal is not unique.

Glial-restricted precursors: Patterns of expression of opioid receptors and relationship to human immunodeficiency virus-1 Tat and morphine susceptibility in vitro

“…Others have shown large temporal discrepancies between caspase activation and cell losses (McEwen and Springer, 2005). Additionally, caspase-3 activation may not necessarily result in cell death (Bellizzi et al, 2006). Another explanation may be that components of Tat-or morphine-mediated apoptotic signaling cascades are not fully developed in GRPs at 1 DIV, although this seems unlikely since caspase-3 activation is one of the final steps in apoptosis (Yuan et al, 2003).…”

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

“…From a therapeutic standpoint, it is important to recognize that synaptic apoptosis and focal losses in dendritic structure and function are not necessarily a prelude to death and in fact may be reversible. 63,[67][68][69] The inducible HIV-1 Tat transgenic mouse appears to be extremely relevant for examining the chronic effects of Tat in HIV-1 neuropathogenesis. The sublethal structural abnormalities observed over the time course of our studies may provide a model for earlier stages of HIV neuropathology that are accompanied by moderate neurological impairment, before the loss of neurons more typical of advanced neuroAIDS.…”

Is Covalently Crosslinked Aβ Responsible for Synaptotoxicity in Alzheimers Disease?

“…Although amyloid plaques and neuronal loss are the most obvious pathological features of AD, recent research has emphasized the importance of soluble A species and synaptotoxicity [2,3,10,11]. As Palop et al points out [10], the fluctuations in neurological function seen in AD patients over short time spans cannot result from the loss or gain of whole nerve cells.…”

“…That is, the main symptoms of AD are due to synaptoxicity and not neurotoxicity. This holds important consequences for the treatment of AD: if early intervention allows synaptic plasticity to be restored, neural networks can recover provided the neuronal cell body survives, arresting or reversing AD symptoms [11]. Synapses and dendrites have been shown to be especially vulnerable to injury compared to cell bodies [12].…”

“…Neurons also show decreased expression of genes related to synaptic vesicle recycling [19], including dynamin 1 [20]. Meanwhile, the characteristic symptoms of AD-chronic inflammation, mitochondrial dysfunction, disrupted calcium homeostasis and oxidative stress-all increase synaptic vulnerability to glutamate excitotoxicity [11]. Many of these effects have been linked directly to the toxic nature of A (see [5,[21][22][23][24][25]).…”