Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice
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Acuña-Catalán, Diego
Shah, Samah
Wehrfritz, Cameron
Nomura, Mitsunori
Acevedo, Alejandro
Olmos, Cristina
Quiroz, Gabriel
Huerta, Hernán
Bons, Joanna
Ampuero, Estibaliz
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Abstract
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<p>Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.</p>
Keywords
BDNF, LTP, PKA, aging, brain-derived neurotrophic factor, ketogenic diet, long-term potentiation, protein kinase A, proteomics, β-hydroxybutyrate