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Neurotrophin receptor p75 affords clearance of amyloid beta in Alzheimer’s disease and provides targeting route to basal forebrain cholinergic neurons

Antyborzec, Inga (2016) Neurotrophin receptor p75 affords clearance of amyloid beta in Alzheimer’s disease and provides targeting route to basal forebrain cholinergic neurons. PhD thesis, Dublin City University.

Basal forebrain cholinergic neurons (BFCNs) are one of the most affected neuronal populations in Alzheimer’s disease (AD). They exclusively express p75 neurotrophin receptor (p75NTR) during adulthood, known also to bind non-neurotrophic ligands including amyloid beta (Aβ), which is mainly responsible for neuronal damage in AD. Immuno-histochemistry and Western blot analysis as well as fluorescent and confocal laser scanning microscopy were utilized in this study to identify and functionally characterize BFCNs in culture and in vivo. Stereotactic injections into the rat brain were used to chemically-induce AD and later to introduce lentivirus targeted to BFCNs. Selective internalization of p75NTR (labelled with 192-IgG-Cy3) and fluorescent (Alexa 488-labelled) Aβ (1-42) was observed in live cultured BFCNs. Parameters of endocytosis and combined trafficking of these two molecules were analyzed as well as their distribution in compartments of BFCNs. Although Aβ entry routes remains elusive, the destination of p75NTR cargo points to lysosomes, suggesting a novel role of p75NTR in Aβ clearance by cholinergic cells. This was also true in saporine-induced (192-IgG-SAP) in vivo AD rat model, in which increase of Aβ (1-42) was observed in cortical and hippocampal structures of brain, thus confirming the role of BFCNs in clearance of Aβ. Interestingly in further experiments Aβ (1-42) oligomers significantly reduced p75NTR endocytosis in a dose-dependent manner, suggesting new homeostatic role of p75NTR in Aβ uptake. P75NTR also prove to facilitate transfer of lentiviral vectors to BFCNs in vitro and vivo. 192-IgG-lentivirus injected into the lateral ventricle of rat brain yielded selective expression of GFP in cholinergic neurons in medial septum and diagonal bands of Brocca regions. New functions of p75NTR described in this thesis make significant contribution to the knowledge of AD. Also novel strategy described herein can be utilized further for targeted delivery of neurotherapeutics to BFCNs with possible minimal off-side effects.
Item Type:Thesis (PhD)
Date of Award:November 2016
Supervisor(s):Dolly, Oliver
Uncontrolled Keywords:neurotherapeutics; BFCNs; Basal forebrain cholinergic neurons; 192-IgG-lentivirus; targeted delivery
Subjects:Biological Sciences > Neuroscience
Medical Sciences > Diseases
DCU Faculties and Centres:UNSPECIFIED
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:21372
Deposited On:16 Nov 2016 11:24 by Oliver Dolly . Last Modified 19 Jul 2018 15:09

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