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Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons

, : Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons. Brain Structure & Function 219(5): 1527-1541

A fascinating yet perhaps overlooked trait of the p75 neurotrophin receptor (p75NTR) is its ability to bind ligands with no obvious neurotrophic function. Using cultured basal forebrain (BF) neurons, this study demonstrates selective internalization of amyloid ? (A?) 1 42 in conjunction with p75NTR (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 p75NTR, 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?. 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? clearance in the cerebral cortex and pathophysiology of Alzheimer s disease is discussed.


PMID: 23716278

DOI: 10.1007/s00429-013-0583-x

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