Leucine-Rich Repeat Kinase 2 Modulates Neuroinflammation and Neurotoxicity in Models of Human Immunodeficiency Virus 1-Associated Neurocognitive Disorders

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is the single most common genetic cause of both familial and sporadic Parkinson's disease (PD), both of which share pathogenetic and neurologic similarities with human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND). Pathologic LRRK2 activity may also contribute to neuroinflammation, because microglia lacking LRRK2 exposed to proinflammatory stimuli have attenuated responses. Because microglial activation is a hallmark of HIV-1 neuropathology, we have investigated the role of LRRK2 activation using in vitro and in vivo models of HAND. We hypothesize that LRRK2 is a key modulator of microglial inflammatory responses, which play a pathogenic role in both HAND and PD, and that these responses may cause or exacerbate neuronal damage in these diseases. The HIV-1 Tat protein is a potent neurotoxin produced during HAND that induces activation of primary microglia in culture and long-lasting neuroinflammation and neurotoxicity when injected into the CNS of mice. We found that LRRK2 inhibition attenuates Tat-induced pS935-LRRK2 expression, proinflammatory cytokine and chemokine expression, and phosphorylated p38 and Jun N-terminal kinase signaling in primary microglia. In our murine model, cortical Tat injection in LRRK2 knock-out (KO) mice results in significantly diminished neuronal damage, as assessed by microtubule-associated protein 2 (MAP2), class III ␤-tubulin TUJ1, synapsin-1, VGluT, and cleaved caspase-3 immunostaining. Furthermore, Tat-injected LRRK2 KO animals have decreased infiltration of peripheral neutrophils, and the morphology of microglia from these mice were similar to that of vehicle-injected controls. We conclude that pathologic activation of LRRK2 regulates a significant component of the neuroinflammation associated with HAND.

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

“…Dopaminergic neurons in the SNpc appear to be particularly sensitive to proinflammatory cytokines, suggesting that the model used here is, at least in part, dependent on proinflammatory responses to kill dopaminergic neurons (33,34). LRRK2 KO rodents show reduced proinflammatory responses in the brain in response to lipopolysaccharide or HIV-trans-activating protein administration (16,35). One mechanism whereby LRRK2 kinase inhibitors could block ␣-synuclein-induced dopaminergic neurotoxicity could be reduction of inflammatory responses known to cause neurodegeneration of dopaminergic cells.…”

Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease

“…Table 1 summarizes studies that involve LRRK2 knockout rodents and LRRK2 kinase inhibitor studies. Protection from LRRK2 knockout and kinase inhibition has been described in models that rely on inflammation as a driving force in dysfunction, for example experimental autoimmune uveitis(Wandu et al, 2015), lipopolysaccharide exposure(Daher et al, 2014), HIV-1 Tat peptide exposure(Puccini et al, 2015), and rhabdomyolysis kidney injury(Boddu et al, 2015). There is some evidence to suggest that inflammation plays a critical role in the rAAV2-WT-hα-synuclein model(Harms et al, 2013; Qin et al, 2016; Van der Perren et al, 2015), and LRRK2 knockouts may be protected from this insult(Daher et al, 2014).…”

Fate of microglia during HIV‐1 infection: From activation to senescence?

“…Microglia activation is also observed using various in vivo models of Tat exposure. For example, microglia activation was detected in mice that were injected with Tat in the striatum for 7 days (El‐Hage et al, ; Puccini et al, ), and in the brain tissues of a rat model 2 weeks post‐stereotaxical Tat injection in the striatum as well (Agrawal et al, ). Microglia activation upon Tat exposure has been reversed with over‐expression of antioxidant enzymes including Cu/Zn superoxide dismutase (SOD1) and glutathione peroxidase (GPx1), suggesting a role of oxidative stress in Tat‐induced microglia activation (Louboutin et al, ; Louboutin and Strayer, ).…”