PMID- 33803798 OWN - NLM STAT- MEDLINE DCOM- 20210507 LR - 20210507 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 13 IP - 3 DP - 2021 Mar 18 TI - Long-Term Caloric Restriction Attenuates beta-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice. LID - 10.3390/nu13030985 [doi] LID - 985 AB - Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates beta-amyloid (Abeta) neuropathology in models of Alzheimer's disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism-a hallmark of AD-and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [(18)F] ([(18)F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Abeta plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Abeta pathology. FAU - Muller, Luisa AU - Muller L AUID- ORCID: 0000-0001-7942-3273 AD - Rudolf-Zenker-Institute for Experimental Surgery, Medical University Rostock, 18057 Rostock, Germany. AD - Department of Psychosomatic Medicine and Psychotherapy, University of Rostock, 18147 Rostock, Germany. AD - Centre for Transdisciplinary Neurosciences Rostock (CTNR), University of Rostock, 18147 Rostock, Germany. FAU - Power Guerra, Nicole AU - Power Guerra N AD - Rudolf-Zenker-Institute for Experimental Surgery, Medical University Rostock, 18057 Rostock, Germany. FAU - Stenzel, Jan AU - Stenzel J AD - Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, 18057 Rostock, Germany. FAU - Ruhlmann, Claire AU - Ruhlmann C AD - Rudolf-Zenker-Institute for Experimental Surgery, Medical University Rostock, 18057 Rostock, Germany. FAU - Lindner, Tobias AU - Lindner T AUID- ORCID: 0000-0001-7826-3132 AD - Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, 18057 Rostock, Germany. FAU - Krause, Bernd J AU - Krause BJ AD - Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, 18057 Rostock, Germany. AD - Department of Nuclear Medicine, Rostock University Medical Center, 18057 Rostock, Germany. FAU - Vollmar, Brigitte AU - Vollmar B AD - Rudolf-Zenker-Institute for Experimental Surgery, Medical University Rostock, 18057 Rostock, Germany. AD - Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, 18057 Rostock, Germany. FAU - Teipel, Stefan AU - Teipel S AD - Department of Psychosomatic Medicine and Psychotherapy, University of Rostock, 18147 Rostock, Germany. AD - Centre for Transdisciplinary Neurosciences Rostock (CTNR), University of Rostock, 18147 Rostock, Germany. AD - German Center for Neurodegenerative Diseases (DZNE)-Rostock/Greifswald, 18147 Rostock and 17489 Greifswald, Germany. FAU - Kuhla, Angela AU - Kuhla A AD - Rudolf-Zenker-Institute for Experimental Surgery, Medical University Rostock, 18057 Rostock, Germany. AD - Centre for Transdisciplinary Neurosciences Rostock (CTNR), University of Rostock, 18147 Rostock, Germany. LA - eng GR - KU3280/1-2/Deutsche Forschungsgemeinschaft/ PT - Journal Article DEP - 20210318 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 0 (Aif1 protein, mouse) RN - 0 (Amyloid beta-Peptides) RN - 0 (Calcium-Binding Proteins) RN - 0 (Microfilament Proteins) RN - 0 (Radiopharmaceuticals) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) RN - 30KYC7MIAI (Aspartic Acid) RN - 997-55-7 (N-acetylaspartate) RN - IY9XDZ35W2 (Glucose) RN - MU72812GK0 (Creatine) SB - IM MH - Alzheimer Disease/*diet therapy/pathology MH - Amyloid beta-Peptides/*metabolism MH - *Animal Nutritional Physiological Phenomena MH - Animals MH - Aspartic Acid/analogs & derivatives/metabolism MH - Autophagy/*physiology MH - Calcium-Binding Proteins/metabolism MH - Caloric Restriction/*methods MH - Cerebral Cortex/metabolism MH - Creatine/metabolism MH - Disease Models, Animal MH - Fluorodeoxyglucose F18 MH - Glucose/metabolism MH - Hippocampus/diagnostic imaging/metabolism MH - Magnetic Resonance Spectroscopy MH - Maze Learning MH - Mice MH - Mice, Inbred C3H MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Microfilament Proteins/metabolism MH - Neurons/physiology MH - Plaque, Amyloid/diet therapy/pathology MH - Positron Emission Tomography Computed Tomography MH - Radiopharmaceuticals PMC - PMC8003277 OTO - NOTNLM OT - APPswe/PS1delta9 OT - [18F]FDG-PET/CT OT - amyloid beta OT - autophagy OT - caloric restriction OT - iba1 COIS- The other authors declare that they have no conflict of interest. EDAT- 2021/04/04 06:00 MHDA- 2021/05/08 06:00 PMCR- 2021/03/18 CRDT- 2021/04/03 01:15 PHST- 2021/02/04 00:00 [received] PHST- 2021/03/09 00:00 [revised] PHST- 2021/03/16 00:00 [accepted] PHST- 2021/04/03 01:15 [entrez] PHST- 2021/04/04 06:00 [pubmed] PHST- 2021/05/08 06:00 [medline] PHST- 2021/03/18 00:00 [pmc-release] AID - nu13030985 [pii] AID - nutrients-13-00985 [pii] AID - 10.3390/nu13030985 [doi] PST - epublish SO - Nutrients. 2021 Mar 18;13(3):985. doi: 10.3390/nu13030985.