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

• Published in: Brain Structure and Function Vol. 219; no. 5; pp. 1527 - 1541
• Main Authors: Ovsepian, Saak V., Antyborzec, Inga, O’Leary, Valerie B., Zaborszky, Laszlo, Herms, Jochen, Oliver Dolly, J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2014; Springer Nature B.V
• Subjects: Age Factors; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Animals; Animals, Newborn; Biomedical and Life Sciences; Biomedicine; Calcium; Cell Biology; Cells, Cultured; Cellular biology; Choline O-Acetyltransferase - metabolism; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; Enzyme Inhibitors - pharmacology; Lysosomal-Associated Membrane Protein 1 - metabolism; Lysosomes - drug effects; Lysosomes - physiology; Neurology; Neurons; Neurosciences; Neurotoxins - pharmacology; Original Article; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptides; Prosencephalon - cytology; Protein Transport - drug effects; rab GTP-Binding Proteins - metabolism; rab7 GTP-Binding Proteins; Rats; Receptor, Nerve Growth Factor - metabolism; Sodium Channel Blockers - pharmacology; Tetrodotoxin - pharmacology; Thapsigargin - pharmacology; Vesicular Transport Proteins - metabolism; Amyloid β clearance; Lysosomal degradation; Calcium; Alzheimer’s disease; Basal forebrain cholinergic neurons; p75 NTR
• ISSN: 1863-2653; 1863-2661; 0340-2061
• DOI: 10.1007/s00429-013-0583-x

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 β (Aβ) 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) Ca
2+
ATPase with thapsigargin and CPA or chelation of Ca
2+
with EGTA-AM strongly suppressed the endocytosis of p75
NTR
, implicating the role of ER released Ca
2+
. The uptake of IgG192-Cy3 was also reduced by T-type Ca
2+
channel blocker mibefradil but not Cd
2+
, an indiscriminate blocker of high voltage-activated Ca
2+
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 Aβ. 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 Aβ clearance in the cerebral cortex and pathophysiology of Alzheimer’s disease is discussed.