Maternal High Fat Diet Anticipates the AD-like Phenotype in 3xTg-AD Mice by Epigenetic Dysregulation of Aβ Metabolism

Francesca Natale; Matteo Spinelli; Marco Rinaudo; Sara Cocco; Ida Nifo Sarrapochiello; Salvatore Fusco; Claudio Grassi

doi:10.3390/cells12020220

Maternal High Fat Diet Anticipates the AD-like Phenotype in 3xTg-AD Mice by Epigenetic Dysregulation of Aβ Metabolism

Cells. 2023 Jan 4;12(2):220. doi: 10.3390/cells12020220.

Authors

Francesca Natale^{1

2}, Matteo Spinelli^{1

2}, Marco Rinaudo^{1

2}, Sara Cocco¹, Ida Nifo Sarrapochiello¹, Salvatore Fusco^{1

2}, Claudio Grassi^{1

2}

Affiliations

¹ Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
² Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy.

Abstract

Maternal overnutrition has been reported to affect brain plasticity of the offspring by altering gene expression, regulating both synaptic plasticity and adult neurogenesis. However, whether perinatal metabolic stress may influence the accumulation of misfolded proteins and the development of neurodegeneration remains to be clarified. We investigated the impact of maternal high fat diet (HFD) in an experimental model of Alzheimer's disease (AD). The 3xTg-AD mice born to overfed mothers showed an impairment of synaptic plasticity and cognitive deficits earlier than controls. Maternal HFD also altered the expression of genes regulating amyloid-β-protein (Aβ) metabolism (i.e., Bace1, Ern1, Ide and Nicastrin) and enhanced Aβ deposition in the hippocampus. Finally, we found an epigenetic derangement and an aberrant recruitment of transcription factors NF-kB and STAT3 and chromatin remodeler HDAC2 on the regulatory sequences of the same genes. Collectively, our data indicate that early life metabolic stress worsens the AD phenotype via epigenetic alteration of genes regulating Aβ synthesis and clearance.

Keywords: Alzheimer’s disease; Bace1; Insulin degrading enzyme; NF-kB; STAT3; amyloid-β-protein; epigenetics; maternal HFD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Amyloid Precursor Protein Secretases / metabolism
Animals
Aspartic Acid Endopeptidases / metabolism
Diet, High-Fat / adverse effects
Epigenesis, Genetic
Mice
Mice, Transgenic

Substances

Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases

Grants and funding

This research was funded by Ministero della Salute—Ricerca Finalizzata (GR-2018-12366381 to S.F.) and by Ministero della Salute—Ricerca Corrente 2022 Fondazione Policlinico Universitario A. Gemelli IRCCS (to C.G.).