Modulatory effect of acetyl-L-carnitine on amyloid precursor protein metabolism in hippocampal neurons.
Alzheimer Disease is the most common chronic neurodegenerative disorder associated with aging. Nevertheless, its pharmacological therapy is still an unresolved issue. In double-blind controlled studies, acetyl-L-carnitine (ALC) demonstrated beneficial effects on Alzheimer's disease. However, the mechanisms behind its neuroprotective ability remain to be fully established. In this study, the effect of acetyl-L-carnitine on amyloid precursor protein (APP) metabolism was investigated by in vitro models, both in a neuroblastoma cell line and in primary hippocampal cultures. We found that ALC treatment stimulates alpha-secretase activity and physiological APP metabolism. In particular, ALC favors the delivery of ADAM10 (a disintegrin and metalloproteinase 10, the most accredited candidate for alpha-secretase) to the post-synaptic compartment, and consequently positively modulates its enzymatic activity towards APP. Our findings suggest that the benefits of ALC reported in previous clinical studies are underscored by the specific biological mechanism of this compound on APP metabolism. In fact, ALC can directly influence the primary event in Alzheimer's disease pathogenesis, i.e. the Amyloid beta cascade, promoting alpha-secretase activity and directly affecting the release of the non amyloidogenic metabolite.
Epis
Roberta
R
Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy.
Marcello
Elena
E
Gardoni
Fabrizio
F
Longhi
Annalisa
A
Calvani
Menotti
M
Iannuccelli
Maurizio
M
Cattabeni
Flaminio
F
Canonico
Pier L
PL
Di Luca
Monica
M
D051722:ADAM Proteins / Q000378:metabolism; D000108:Acetylcarnitine / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D021381:Protein Transport; D051381:Rats; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D000108:Acetylcarnitine; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins