Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity

Abstract

Many recent studies indicate that dysregulation of autophagy is a common feature of many neurodegenerative diseases. The HIV-1-associated neurological disorder is an acquired cognitive and motor disease that includes a severe neurodegenerative dementia. We find that the neurodegeneration seen in the brain in HIV-1 infection is associated with an inhibition of neuronal autophagy, leading to neuronal demise. Neurons treated with supernatants from SIV-infected microglia develop a decrease in autophagy-inducing proteins, a decrease in neuronal autophagy vesicles, and an increase in sequestosome-1/p62. Examination of brains from HIV-infected individuals and SIV-infected monkeys reveals signs of autophagy dysregulation, associated, respectively, with dementia and encephalitis. Excitotoxic and inflammatory factors could inhibit neuronal autophagy, and stimulation of autophagy with rapamycin prevents such effects. Here we amplify on these findings, and propose that in the setting of HIV-infection, the decreased neuronal autophagy sensitizes cells to pro-apoptotic and other damaging mechanisms, leading to neuronal dysfunction and death. Hence, new therapeutic approaches aimed at boosting neuronal autophagy are conceivable to treat those suffering from the neurological complications of HIV.

Figure 1

(Top) IMARIS analysis of confocal images of primary neurons, delineating subcellular structures. Autophagy vesicles (green dots), mitochondria (red dots), and the nucleus (blue) are shown in this neuron. (Bottom) Flattened confocal images of the neuron shown above, which has been co-transfected with GFP-LC3 to label AV and DsRed-Mito to label mitochondria, and reacted with DAPI for nuclear staining.

Figure 2

AV counts in undifferentiated (left) and dopaminergic differentiated (RA+TPA) SH-SY5Y cells (right), treated (Sup), or not (control), with supernatant from SIV-infected microglia. In both cases, the number of AV is significantly increased (p<0.001, t-test).

Figure 3

Schematic illustration of interaction between HIV-infected microglia, other glia, and neurons in neuroAIDS. HIV-infected microglia, as well as activated/reactive microglia and astrocytes, produce molecules that lead to a pro-inflammatory and excitotoxic environment, resulting in an NMDAR-dependent mechanism leading to neuronal injury and death. Glutamate activation of the NMDAR leads to calcium influx into the neuron, calpain activation, suppression of autophagy, and enhancement of apoptotic pathways, leading to neuronal demise.