Hippocampal proliferation is increased in presymptomatic Parkinson's disease and due to microglia - PubMed (original) (raw)

Hippocampal proliferation is increased in presymptomatic Parkinson's disease and due to microglia

Karlijn J Doorn et al. Neural Plast. 2014.

Abstract

Besides dopamine-deficiency related motor symptoms, nonmotor symptoms, including cognitive changes occur in Parkinson's disease (PD) patients, that may relate to accumulation of α-synuclein in the hippocampus (HC). This brain region also contains stem cells that can proliferate. This is a well-regulated process that can, for example, be altered by neurodegenerative conditions. In contrast to proliferation in the substantia nigra and subventricular zone, little is known about the HC in PD. In addition, glial cells contribute to neurodegenerative processes and may proliferate in response to PD pathology. In the present study, we questioned whether microglial cells proliferate in the HC of established PD patients versus control subjects or incidental Lewy body disease (iLBD) cases as a prodromal state of PD. To this end, proliferation was assessed using the immunocytochemical marker minichromosome maintenance protein 2 (MCM2). Colocalization with Iba1 was performed to determine microglial proliferation. MCM2-positive cells were present in the HC of controls and were significantly increased in the presymptomatic iLBD cases, but not in established PD patients. Microglia represented the majority of the proliferating cells in the HC. This suggests an early microglial response to developing PD pathology in the HC and further indicates that neuroinflammatory processes play an important role in the development of PD pathology.

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Figures

Figure 1

Figure 1

_α_-Synuclein pathology present in the hippocampus of PD cases. (a-b) _α_-Synuclein immunoreactivity (IR) in CA of control and iLBD subjects is absent compared to (c) _α_-synuclein IR (LBs: arrow, LNs: arrowhead) in the CA region of PD patients; bar (a–c) = 100 _μ_m; higher magnification (c′) bar = 20 _μ_m.

Figure 2

Figure 2

MCM2-positive cells in the hippocampal CA3 region of an iLBD case. High magnification of MCM2 IR reveals clear examples of doublets (arrows). The MCM2-positive cell indicated with the arrowhead is closely opposed to a large pyramidal neuron; bar = 25 _μ_m.

Figure 3

Figure 3

MCM2-positive cell numbers in control subjects, iLBD cases, and PD patients. Semiquantitative analysis revealed that in (a) control subjects, a significant main effect was present (P = 0.034; related nonparametric Friedman's analysis) with higher numbers of MCM2-positive cells in the DG compared to the hippocampal subregions (DG versus CA3 and CA4 # P = 0.043; DG versus CA1 P = 0.08 n.s.; DG versus CA2 P = 0.225 n.s.; nonparametric paired Wilcoxon post hoc test). (b, c) In the iLBD and PD cases, no differences were present between any of the subregions. Significance reached at alpha of P ≤ 0.02, FWE-corrected. Data represent mean ± SEM.

Figure 4

Figure 4

MCM2-positive cell numbers in the total HC and different hippocampal subregions. (a) The total number of MCM2-positive cells in the HC was significantly higher in iLBD cases compared to control subjects (*P = 0.004; nonparametric Mann-Whitney U test). (b–f) Comparing MCM2 IR per HC subregion between the 3 different groups revealed a significant increase in number of proliferating cells in hippocampal areas (d) CA3 and (e) CA4 (resp., *P = 0.001, *P = 0.003; nonparametric Mann-Whitney U test) of iLBD cases versus control subjects. Significance reached at alpha of P ≤ 0.016, Bonferroni-corrected. Data represent mean ± SEM.

Figure 5

Figure 5

Colocalization of the majority of MCM2-positive cells with Iba1 in the hippocampal CA3 region of control subjects, iLBD cases and PD patients. (a–f) Representative confocal laser scanning microscopical images of double-immunofluorescent stained sections revealed that the majority of the MCM2-positive cells show colocalization with the microglial marker Iba1 (arrows in (c), (f), (i) and (j), and (k) and (l)). Iba1-positive microglia are depicted in green (a, d, and g) and MCM2 in red (b, e, and h). (j–l) Higher magnification of colocalization (l) between Iba1-positive microglia ((j), green) and MCM2 ((k), red); bar (a–i) = 40 _μ_m; (j–l) = 10 _μ_m.

Figure 6

Figure 6

Colocalization of the majority of MCM2-positive cells with Iba1 in the hippocampal DG region of control subjects, iLBD cases, and PD patients. (a–f) Representative confocal laser scanning microscopical images of double-immunofluorescent stained sections revealed that the majority of the MCM2-positive cells show colocalization with the microglial marker Iba1 (arrows in (c), (f), and (i)). (b, d) Control subject shows one MCM2-positive cell with no colocalization with Iba1 (arrowhead). Iba1-positive microglia are depicted in green (a, d, and g) and MCM2 in red (b, e, and h); bar (a–i) = 40 _μ_m.

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