Parkinson's Disease: Can Targeting Inflammation Be an Effective Neuroprotective Strategy?

Abstract

The reason why dopamine neurons die in Parkinson's disease remains largely unknown. Emerging evidence points to a role for brain inflammation in neurodegeneration. Essential questions are whether brain inflammation happens sufficiently early so that interfering with this process can be expected to slow down neuronal death and whether the contribution from inflammation is large enough so that anti-inflammatory agents can be expected to work. Here I discuss data from human PD studies indicating that brain inflammation is an early event in PD. I also discuss the role of T-lymphocytes and peripheral inflammation for neurodegeneration. I critically discuss the failure of clinical trials targeting inflammation in PD.

Keywords: T-cells; alpha-synuclein; brain; cervical lymph node; gut; microglia.

FIGURE 1

The root cause of PD is unknown, but inflammation is probably an early damaging event in PD. Probably genetic and/or environmental factors contribute to starting the α-synuclein pathology in dopamine neurons. In physiology α-synuclein (“normal α-synuclein”) is transported from the SNc along axons to nerve terminals in the striatum where it is important for synaptic transmission. In dysfunctional dopamine neurons α-synuclein is misfolded into oligomers (“misfolded α-synuclein oligomer”), which can be secreted into the interstitium. This aberrant α-synuclein can activate microglia, in turn starting an inflammatory process through in particular IL-6 and IL-1β. Whether TNF-α works at early PD stages has not been investigated, but TNF-α is involved in sustained brain inflammation. INF-γ may also be part of the sustained inflammatory response, but the data for this are less robust. These cytokines can potentiate the toxic effect on dopamine neurons and the neurodegenerative process, ultimately leading to aggregation of α-synuclein in Lewy bodies and neuronal death. The anti-inflammatory TGF-β, and perhaps IL-10, are probably secreted to counteract the toxic effects of the pro-inflammatory cytokines. However, in PD, the toxic effects seem to prevail. The effect of activated microglia and cytokine release on the death of dopamine neurons is not known for the human brain. A cue may be achieved by studying human iPSC microglia–neuron co-cultures.

FIGURE 2

Proposed time course and the action of microglia and CD4+ and CD8+ T-cells on degeneration of dopamine neurons in PD. (A) Probably as an initial event in PD pathogenesis dysfunctional dopamine neurons secrete misfolded α-synuclein oligomers, which can activate microglia (see Figure 1). Next, activated microglia phagocytose this α-synuclein and present aberrant α-synuclein peptides via MHC class II molecules to CD4+ T-cells. It is well established that activated microglia present antigens on MHC II, but which type of antigens that are presented in the human PD brain is not known. Activated microglia release pro-inflammatory cytokines, including INF-γ (see Figure 1). The cytokines are toxic to dopamine neurons, further augmenting the pathology. INF-γ can increase the expression of MHC class II on microglia and MHC class I on dopamine neurons. (B) Priming of CD4+ T-cells, as well as of CD8+ T-cells, happens after microglia activation, but exactly when in the time course of PD progression is not known. Whether priming of CD4+ and CD8+ T-cells occurs within or outside (see Figure 3) the PD brain is not clarified. INF-γ, which can be secreted also from primed CD4+ T-cells, sustains the activated phenotype of microglia and further increases the expression of MHC class II on microglia and MHC class I on dopamine neurons. This will stimulate the priming process. Besides INF-γ, primed CD4+ T-cells may secrete TNF-α and primed CD8+ T-cells may release secretory granules, both of which may be toxic to neurons. But if these T-cell mediated toxicities take place in the brain of PD patients is not known. TCR, T-cell receptor.

FIGURE 3

Possible peripheral sites of α-synuclein induced activation of T-cells. (1) Misfolded α-synuclein oligomers are secreted from dopamine neurons in the SNc into the intersitium. From here α-synuclein can flow via the glymphathic system to the CSF and into meningeal lymph vessels and reach cervical lymph nodes (red filled arrows). Here α-synuclein may be phagocytosed by antigen presenting cells (APC) and presented to CD4+ T-cells via MHC class II and T-cell receptors (TCRs), leading to priming of the T-cells. These T-cells can enter the circulation, cross the blood brain barrier (BBB) and patrol the brain parenchyma. Extracellular α-synuclein, released from dopamine neurons, will also activate microglia (red dotted arrow). Microglia will expose α-synuclein on MHC class II. When patrolling T-cells meet antigen presenting microglia they may be reactivated, which in turn may lead to increased brain inflammation. Meninges: P, pia mater; A, arachnoidea; D, dura mater; (2) CD4+ T-cells could be primed in the gut. Local pathology, such as inflammation, may cause α-synuclein to misfold and aggregate in gut neurons. This misfolded α-synuclein could be secreted (black filled arrow) and end up in MHC class II on APCs. This will prime CD + T-cells, which then may gain access to the brain via the circulation in the same manner as T-cells primed in cervical lymph nodes. The finding of α-synuclein reactive T-cells in the blood of PD patients is consistent with scenarios (1) and (2). (3) Misfolded α-synuclein can be trans-synaptically taken up by the vagus nerve and retrogradely transported to the dorsal motor nucleus of the vagus (black dotted arrows). As this nucleus is not directly interconnected with the SNc, α-synuclein can reach SNc through trans-synaptical and retrograde spread via several brain regions. Thus, misfolded α-synuclein from gut neurons may cause templating in dopamine neurons, leading to aggregation of α-synuclein in dysfunctional neurons, inflammation, and ultimately neuronal death.