Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

Abstract

Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) 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 [18F] ([18F]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 Aβ 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 Aβ pathology.

Effects of acute ethanol and/or diazepam exposure on immediate and delayed hippocampal metabolite levels in rats anesthetized with isoflurane

“…A decrease in NAA levels is usually described in pathological conditions in clinical [27,28,33,34] and preclinical studies [35–37]. Our results in the EtOH group may therefore appear discordant with, on the one hand, a decrease in GABA/glutamate, which seems to reflect an impairment, and on the other, an increase in NAA, which could reflect an improvement in neuronal integrity [38]. However, this could reflect a repair process.…”

Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model

“…To the best of our knowledge, the spine density of elderly people with insufficient protein intake has not been investigated thus far, but analogous to this result, there is a possibility that spine density in the brain has decreased in these populations as well. When discussing relationships between food intake and the brain, there are recent reports indicating that caloric restriction (CR) has positive effects on longevity and neurodegenerative diseases in animal studies (32)(33)(34). Müller et al (34) indicated that CR attenuated  amyloid deposition and increased autophagy in an AD model.…”

“…When discussing relationships between food intake and the brain, there are recent reports indicating that caloric restriction (CR) has positive effects on longevity and neurodegenerative diseases in animal studies (32)(33)(34). Müller et al (34) indicated that CR attenuated  amyloid deposition and increased autophagy in an AD model. In our experiments, caloric intake did not differ much in any group, and our data showed that autophagy in rTg4510 mice was not affected under either food condition (fig.…”

Disentangling Mitochondria in Alzheimer’s Disease

“…A CR dietary regimen prevented Aβ peptide production and plaque deposition in multiple models of AD, leading to the reduction of neuronal loss in the hippocampus and the improvement of cognitive deficits [ 332 , 333 , 334 , 335 , 336 , 337 , 338 ]. Mechanisms triggered by CR include promotion of anti-amyloidogenic alpha-secretase activity and induction of the NAD + -dependent Sirt1 deacetylase and autophagy [ 332 , 334 , 339 , 340 ]. Both animal and human studies have shown that CR benefits general health, improves memory and cognition, and slows down the aging process.…”