TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid β-Protein Generation in Neurons. (15th March 2019)

• Record Type: Journal Article
• Authors: Yamamoto, Fumiko; Taniguchi, Kaori; Mamada, Naomi; Tamaoka, Akira; Kametani, Fuyuki; Lakshmana, Madepalli K.; Araki, Wataru
• Is Part Of: Neuroscience. Volume 402(2019)
• Page Start: 11
• Page End: 22
• Publication Date: 2019-03-15
• Subjects: AD Alzheimer's disease -- ALP autophagy-lysosomal pathway -- APP amyloid precursor protein -- Aβ amyloid β-protein -- CQ chloroquine -- CTF C-terminal fragment -- DIV days in vitro -- Epo epoxomicin -- LAMP-1 lysosome-associated membrane protein-1 -- PS1, 2 presenilin 1, 2 -- TFEB transcription factor EB; Aβ -- ADAM10 -- Alzheimer -- autophagy-lysosomal pathway -- neuron -- TFEB; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.01.010
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: TFEB enhanced ADAM10 protein levels, but did not affect those of APP, BACE1, or γ-secretase complex components. TFEB augmented β-CTF levels possibly through altered proteasome-mediated catabolism. TFEB decreased the amount of secreted Aβ under the basal condition, but increased it when APP or β-CTF was co-overexpressed. TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aβ production in neurons. Abstract: Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid β-protein (Aβ) generation in neurons. TFEB was overexpressed in mature rat primary cortical neurons via recombinant adenoviruses, without (basal conditions) or with co-overexpression of wild-type amyloid precursor protein (APP) or its β-C-terminal fragment (β-CTF). We confirmed that TFEB overexpression upregulated the lysosomal proteins, cathepsin D and LAMP-1. In TFEB-expressing neurons, protein levels of ADAM10 were profoundly increased, whereas those of APP, BACE1, or γ-secretase complex proteins were unaffected. However, TFEB did not affect ADAM10 mRNA levels. TFEB overexpression had different effects on Aβ production depending on the expression level of APP or β-CTF: TFEB slightly decreased Aβ secretion under basal conditions; clearly increased α-CTF levels and marginally increased β-CTF levels with modest increases in secreted Aβ in APP-expressing neurons; and caused a remarkable increase in β-CTF levels with a significant increase in secreted Aβ in β-CTF-expressing neurons. Inhibition of proteasomes, but not lysosomes, markedly increased β-CTF levels in β-CTF-expressing neurons. These results collectively indicate that TFEB modulates Aβ production not only by increasing α-secretase processing of APP through ADAM10 upregulation but also by augmenting β-CTF levels possibly via altered proteasome-mediated catabolism. Thus, TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aβ production in neurons.