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Open Access Green as soon as Postprint is submitted to ZB.
Neurotrophin receptor p75 mediates the uptake of the amyloid beta (A β) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons.
Brain Struct. Funct. 219, 1527-1541 (2014)
A fascinating yet perhaps overlooked trait of the p75 neurotrophin receptor (p75(NTR)) is its ability to bind ligands with no obvious neurotrophic function. Using cultured basal forebrain (BF) neurons, this study demonstrates selective internalization of amyloid beta (A beta) 1-42 in conjunction with p75(NTR) (labelled with IgG192-Cy3) by cholinergic cells. Active under resting conditions, this process was enhanced by high K+ stimulation and was insensitive to inhibitors of regulated synaptic activity-tetrodotoxin or botulinum neurotoxins (BoNT type/A and/B). Blockade of sarco-endoplasmic reticulum (SERCA) Ca2+ ATPase with thapsigargin and CPA or chelation of Ca2+ with EGTA-AM strongly suppressed the endocytosis of p75(NTR), implicating the role of ER released Ca2+. The uptake of IgG192-Cy3 was also reduced by T-type Ca2+ channel blocker mibefradil but not Cd2+, an indiscriminate blocker of high voltage-activated Ca2+ currents. A strong co-localization of IgG192-Cy3 with late endosome (Rab7) or lysosome (Lamp1) qualifier proteins suggest these compartments as the primary destination for internalized IgG192 and A beta. Selective uptake and labeling of BF cholinergic cells with IgG192-Cy3 injected into the prefrontal cortex was verified also in vivo. The significance of these findings in relation to A beta clearance in the cerebral cortex and pathophysiology of Alzheimer's disease is discussed.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
P75 Ntr ; Basal Forebrain Cholinergic Neurons ; Lysosomal Degradation ; Calcium ; Amyloid Beta Clearance ; Alzheimer's Disease; Nerve Growth-factor; Retrograde Axonal-transport; Long-term Potentiation; Alzheimers-disease; Botulinum Neurotoxin; In-vivo; Calcium Currents; Ca2+ Channels; Tetanus Toxin; P75(ntr)
ISSN (print) / ISBN
1863-2653
e-ISSN
1863-2661
Journal
Brain Structure & Function
Quellenangaben
Volume: 219,
Issue: 5,
Pages: 1527-1541
Publisher
Springer
Publishing Place
Berlin ; Heidelberg
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Radiation Biology (ISB)