Elevated glial brain-derived neurotrophic factor in Parkinson's diseased nigra☆
Introduction
Idiopathic Parkinson's disease (IPD) is characterised by degeneration of dopaminergic (DAergic) striatal projection neurons in the lateral and ventral substantia nigra pars compacta (SNc) [20], [27] and gliosis [21], [22], [54], [55]. Current treatments elevate striatal dopamine content but do not prevent DAergic neuron degeneration nor abate disease progression. There is ample evidence from cell culture and in vivo experiments to indicate a potential neuroprotective role for neurotrophins [3], [37], [39], [85], [86] including brain derived neurotrophic factor (BDNF) [3], [10], [23], [36], [37], [87], [95], neurotrophin-3 (NT-3) [23], [37], [65], neurotrophin-4/5 (NT-4/5) [8], [30], [31], [93] and glial cell line neurotrophic factor (GDNF) [11], [42], [51], [53], [79], [88] in IPD.
Dopaminergic neurons in the rodent SNc express messenger RNA (mRNA) for BDNF and NT-3 [81] which declines following 6-hydroxydopamine (6-OHDA) lesion [82], [91]. The high affinity tyrosine kinase receptors (abbreviated as ‘trk’ in rodents and ‘TRK’ in humans), trkB and trkC are also expressed in the SNc and caudate-putamen (CaPu) [4], [6], [59], [70] where trkB mRNA expression is elevated following 6-OHDA lesion in rodents [69]. The CaPu does not contain detectable amounts of BDNF or NT-3 mRNA [2], [57], [80] but protein is present for both BDNF [16], [41], [63], [80], [95] and NT-3 [99] due to anterograde transport from cortical or nigral projection fibres [2], [5].
A recent study in humans found NGF, BDNF, NT-3, TRKA, TRKB or TRKC immunoreactivity (IR) in a higher percentage of medial compared with lateral SNc DAergic neurons [68]. Subsequently, a reduced number of BDNF-IR melanised neurons have been reported in parkinsonian, compared with control nigra [73]. TrkB mRNA expression in DAergic neurons was similar in parkinsonian and control nigra [12] however.
Nigral astrogliosis [21], [22] and microgliosis [46], [47], [55], [56] are pathological hallmarks of IPD. We recently reported an up-regulation of ramified microglia and an influx of amoeboid microglia within the astrocyte envelope surrounding fragmenting but not healthy neurons in IPD [46] suggesting that glia are strategically placed to signal to failing neurons. The presence of mRNA and proteins for NT-3, BDNF, NGF and trks has been demonstrated in rat astrocytes and microglia in culture [58], [66], [75], [89], [96]. If this is also the case in vivo in humans, glia might contribute to local neurotrophin supply or storage. To our knowledge there are no studies comparing neurotrophin or TRK receptor proteins in glia of human control and parkinsonian nigra. We have therefore examined the cellular distribution of immunoreactivity for BDNF and NT-3, TRKB and TRKC in post-mortem SNc and CaPu of parkinsonian and neurologically normal subjects in order to establish whether local glia are able to offer any neurotrophin assistance to vulnerable nigral neurons and whether changes in neuronal or glial TRK receptors occur in IPD.
Section snippets
Clinical details
Substantia nigra from 11 patients with a post-mortem neuropathological diagnosis of IPD (aged 67–84 years; 7 male) and nine control subjects with no neurological disease (aged 63–85 years; 4 male) were studied. The post-mortem delay for both groups ranged from 4.83 to 47.5 h. There was no significant difference in either age (p>0.9) or post-mortem delay interval (p>0.9) between groups. Tissue pH, which reflects agonal state severity [33], was measured as part of our routine assessment of
Data analysis
In order to make objective semi-quantitative comparisons of the relative stain intensity of neuronal somata, glial somata and neuropil (which contains processes of both neurons and glia) in control and IPD groups, all sections for each antigen were processed side by side under the same conditions and photographed under the same lighting and magnification conditions. The transparencies were scanned (Nikon coolscan II) with no alteration in image and digitised images were saved in TIFF format and
Astrocyte and microglial distribution
GFAP-IR astrocyte processes enveloped somata and processes of nigral neurons and CaPu neurons in IPDs and controls as reported previously [46]. In IPDs, where fragmented melanised neurons were present in the ventral SNc, EBM11-IR amoeboid microglia infiltrated the astrocyte envelope surrounding the neuronal somata and EBM11-IR ramified microglia were present in the surrounding neuropil. In areas of extensive neuronal degeneration, neuromelanin deposits, GFAP-IR astrocytes and EBM11-IR amoeboid
Normal distribution of neurotrophins and their receptors
The distribution of BDNF-, NT-3-, TRKB- and TRKC-like immunoreactivity that we observed in normal human SN and CaPu reflects closely that found previously in the rat [16], [24], [41], [94], [95], [98], [99] and human [63], [68], [73]. Protein and mRNA for these molecules has also been demonstrated in rodent [90], [96] and human [92] astroglial cultures and rodent microglial cultures [19]. Accordingly, BDNF-IR was present in melanised nigral neurons, where mRNA levels are high [82], and in
Acknowledgements
We wish to thank the Parkinson's Disease Society for their financial support, the Parkinson's Disease Society Research Centre (Brain Bank) for provision of human post-mortem brain tissue, Mrs Linda Elliott for sectioning and Dr S.E. Daniel for her expert neuropathological evaluation of the material.
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2014, NeuroscienceCitation Excerpt :Previous studies showed ameboid microglia in the classically affected brain regions of Parkinson and Alzheimer patients. In idiopathic Parkinsońs disease, glial cells including ameboid microglia were suggested to up-regulate neurotrophins such as BDNF in response to signals released from failing nigral neurons (Knott et al., 2002). Furthermore, despite the observed pathological alterations in neurite morphology, neuronal loss was not apparent in the anterior olfactory nucleus of Parkinson and Alzheimer patients, indicating that synaptopathy may precede neuronal cell death (Doorn et al., 2014).
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Delay in publication due to manuscript being lost in transit.