Oligodendrocytes are a Novel Source of Amyloid Peptide Generation

Alzheimer’s disease is characterised by regional neuronal degeneration, synaptic loss, and the progressive deposition of the 4 kDa β-amyloid peptide (Aβ) in senile plaques and accumulation of tau protein as neurofibrillary tangles. Aβ derives from the larger precursor molecule, amyloid precursor protein (APP) by proteolytic processing via β- and γ-secretases. While APP expression is well documented in neurons and astrocytes, the case for oligodendrocytes is less clear. The latter cell type is reported to express different isoforms of APP, and we have confirmed this observation by immunocytochemistry in cultures of differentiated rat cortical oligodendrocytes. Moreover, by means of a sensitive electrochemiluminescent immunoassay employing Aβ C-terminal specific antibodies, mature oligodendrocytes are shown to secrete the 40 and 42 amino acid Aβ species (Aβ40 and Aβ42). Secretion of Aβ peptides was reduced by incubating oligodendrocytes with α- and β-secretase inhibitors, or a γ-secretase inhibitor. Disturbances of APP processing and/or synthesis in oligodendrocytes may account for some myelin disorders observed in Alzheimer’s disease and other senile dementias.