Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression.
Sorting protein-related receptor with A-type repeats (SORLA) is a major risk factor in cellular processes leading to Alzheimer's disease (AD). It acts as sorting receptor for the amyloid precursor protein (APP) that regulates intracellular trafficking and processing into amyloidogenic-beta peptides (A beta). Overexpression of SORLA in neurons reduces while inactivation of gene expression (as in knock-out mouse models) accelerates amyloidogenic processing and senile plaque formation. The current study aimed at identifying molecular pathways that control SORLA gene transcription in vivo and that may contribute to low levels of receptor expression in the brain of patients with AD. Using screening approaches in primary neurons, we identified brain-derived neurotrophic factor (BDNF) as a major inducer of Sorla that activates receptor gene transcription through the ERK (extracellular regulated kinase) pathway. In line with a physiological role as regulator of Sorla, expression of the receptor is significantly impaired in mouse models with genetic (Bdnf(-/-)) or disease-related loss of BDNF activity in the brain (Huntington's disease). Intriguingly, exogenous application of BDNF reduced A beta production in primary neurons and in the brain of wild-type mice in vivo, but not in animals genetically deficient for Sorla. These findings demonstrate that the beneficial effects ascribed to BDNF in APP metabolism act through induction of Sorla that encodes a negative regulator of neuronal APP processing.
Rohe
Michael
M
Max Delbrueck Center for Molecular Medicine, Charité-Universitätsmedizin Berlin, D-13125 Berlin, Germany.
Synowitz
Michael
M
Glass
Rainer
R
Paul
Steven M
SM
Nykjaer
Anders
A
Willnow
Thomas E
TE
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C491168:Sorl1 protein, mouse; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases