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From the two central nodes in the anabolism\u2013catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 5\u2032\u2010monophosphate (AMP)\u2010activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (A\u03b2) production disturbs the optimal neuronal\/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation\/degradation of \u03b2\u2010amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)\/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced A\u03b2 secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on A\u03b2 secretion. Conversely, AMPK inhibition did not affect autophagy but reduced A\u03b2 secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented A\u03b2 secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy\u2010dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction.<\/jats:p>","DOI":"10.1002\/glia.24492","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T22:42:27Z","timestamp":1701124947000},"page":"588-606","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Clearance of \u03b2\u2010amyloid mediated by autophagy is enhanced by <scp>MTORC1<\/scp> inhibition but not <scp>AMPK<\/scp> activation in <scp>APP<\/scp>\/<scp>PSEN1<\/scp> astrocytes"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8958-0504","authenticated-orcid":false,"given":"Marta","family":"Garc\u00eda\u2010Juan","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d (CSIC\u2010UAM), Nicolas Cabrera 1 Universidad Aut\u00f3noma de Madrid  Madrid 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