Relationship of neighboring tissue and gliosis to α-synuclein pathology in a fetal transplant for Parkinson's disease

Abstract

Background: Fetal transplantation for Parkinson disease (PD) had been considered a promising therapeutic strategy; however, reports of Lewy bodies (LBs) and Lewy neurites (LNs) in engrafted tissue adds to controversy surrounding this treatment for PD.

Methods: The brain of a PD patient who had fetal transplantation 14 years before death was evaluated. The graft was studied with routine histologic methods, as well as immunohistochemistry for α-synuclein, neurofilament, synaptophysin and tyrosine hydroxylase (TH), as well as glial fibrillary acidic protein (GFAP) for astrocytes and ionized calcium-binding adaptor molecule 1 (IBA-1) for microglia.

Results: On coronal sections of the brain, the graft extended from the putamen to the amygdala, abutting the anterior hippocampus. Microscopically, the graft consisted of neuron-rich and glia-rich portions. Neuron-rich portions, resembling a neuronal heterotopia, were located in the putamen, whereas the glia-rich portion was more ventral near the amygdala. LBs and LNs were detected in the ventral portion of the graft, especially that part of the graft within the amygdala. Areas with LBs and LNs also had astrogliosis and microgliosis. TH positive neurons were rare and their distribution did not overlap with LBs or LNs.

Comments: LBs and LNs were detected in the transplanted tissue with α-synuclein immunohistochemistry. Unexpected outgrowth of the graft into the amygdala was accompanied by skewed distribution of LBs and gliosis, more abundant in the graft within the amygdala. The distribution of LBs within the graft may suggest the potential role of the local environment as well as gliosis in formation of α-synuclein pathology.

Keywords: Fetal transplantation; Parkinson disease (PD); gliosis; therapy; α-synuclein pathology.

Figure 1

Macroscopic appearance of graft and surrounding host tissue.

Figure 2

A) GFAP immunohistochemistry. Scale bar = 3 mm; B-1) ‘Neuronal heterotopia’ in the putaminal portion ofthe graft; Neuronal cluster (*) is surrounded by glia dominant tissue (arrowheads). Scale bar = 50 μm; B-2) Neuroma-like tissue in the amygdala portion of the graft; Only a few scattered neurons are visible among the glial cells.Scale bar = 50 μm; C-1) Rare GFAP (+) processes in the putaminal portion of the graft (‘neuronal heterotopia’) Scalebar = 50 μm; C-2) Abundant GFAP (+) processes in the amygdala portion of the graft (‘neuroma’). Scale bar = 50 μm.

Figure 3

A) LFB staining. Some thick bundle of myelinated fibers (arrows) seen around neuron-rich portions of graft(*). Scale bar= 300 μm; B-1) PAS (+) lipofuscin found in almost all neurons (host, amygdala); B-2) Rare smallamounts of PAS (+) lipofuscin (arrows) in a neuronal heterotopia Scale bar=50 μm; C) Corpora amylacea, yellow dots.

Figure 4

IBA-1: A) IBA-1 (activated forms, red dots); B) Activated microglia in the graft. Scale bar = 50 μm.

Figure 5

SMI-31 (phosphorylated neurofilament). A) low power view of graft and surrounding tissue; B-1) area of graft with few neurons (*) Scale bar = 50 μm; B-2) area of graft with many neurons (arrowhead) Scale bar = 50 μm; B-3) host tissue (amygdala; black box). Scale bar = 50 μm.

Figure 6

Synaptic markers. A) SNAP25; B) α-synuclein. LBs (host and graft), blue dots.

Figure 7

TH. A) TH positive neurons, red dots. B) TH positive neurons (* in A) Scale bar = 50 μm; C) TH positive fibers (# in A) Scale bar = 50 μm.

Figure 8

A) α-synuclein: cortical type LBs (arrows)and glial inclusions (arrowheads). Scale bar = 20μm; B) Double immunohistochemistry for GAD and α-synuclein: GAD: BCIP - blue; α-synuclein: DAB - brown. Scale bar = 20 μm; C) Double immunohistochemistryfor GFAP and α-synuclein: GFAP: BCIP - blue; α-synuclein: DAB - brown. Scale bar = 20 μm.

Figure 9

Amygdala portion of graft. A-1) SNAP25-poor area Scale bar = 50 μm; A-2) NACP in SNAP25-poor area Scalebar = 50 μm; B-1) SNAP25-rich area Scale bar = 50 μm; B-2) α-synuclein in SNAP25-rich area. Scale bar = 50 μm.