Caloric restriction (CR) decelerates the aging process, extends lifespan and exerts neuroprotective effects in diverse species by so far unknown mechanisms. Based on known neuroprotective effects of fibroblastic growth factor 21 (Fgf21) we speculate that CR upregulates Fgf21, which phosphorylates neuronal AMP-activated protein kinase (AMPK), leading to a decrease of mammalian target of rapamycin (mTOR) signaling activity and an inhibition of tau-hyperphosphorylation. This in turn reduces the formation of neurofibrillary tangles, a neuropathological hallmark of Alzheimer's disease. ApoE-deficient mice (ApoE−/−), serving as a model of neurodegeneration, showed upon CR vs. ad libitum feeding increased Fgf21 levels in both, plasma and brain as well as higher phosphorylation of fibroblastic growth factor receptor 1c (Fgfr1c), extracellular signal-regulated kinases 1/2 (ERK1/2) and AMPK in brain, lower activity of mTOR and decreased Tau-phosphorylation. Finally, CR in ApoE−/− mice caused neuroprotection as indicated by a higher synaptic plasticity shown by immunohistochemical analysis with increased numbers of PSD95-positive neurons and a better cognitive performance as analyzed with Morris water maze test. These data provide substantial evidence that neuroprotection upon CR seems to be Fgf21-dependent. Further experiments are necessary to evaluate Fgf21 as a therapeutic tool to treat tauopathy for improvement of cognitive performance.

Epidemiological studies suggest that individuals with diabetes mellitus are at greater risk of developing Alzheimer's disease. A well-known insulin-sensitizing drug and the most widely prescribed oral medication for diabetes is metformin. There is evidence that metformin acts in a neuroprotective manner via the AMPK/mTOR pathway by inhibiting the tau phosphorylation. In addition, it is known that metformin upregulates Fgf21, which in turn activates the AMPK/mTOR pathway and mediates neuroprotection. Thus, metformin-induced Fgf21 release may be involved in AMPK/mTOR activation. However, some studies reported that metformin causes cognition impairment. Due to the controversial data on the neuroprotective properties of metformin, we treated Apolipoprotein E deficient (ApoE-/-) mice, a mouse model of tauopathy, with metformin for 18 weeks. Metformin-treated mice revealed increased expression of lipogenic genes, i.e., lxr␣ and srebp1c. In line with this, metformin caused an increase in plasma triglyceride leading to enhanced gliosis as indicated by an increase of GFAP-positive cells. Although the systemic Fgf21 concentration was increased, metformin did not activate the FgfR1c/AMPK/mTOR pathway suggesting a Fgf21-resistant state. Further, metformin-treated mice showed increased tau phosphorylation and reduced numbers of NeuN-and PSD95-positive cells. Thus, metformin-associated lipogenesis as well as inflammation aggravated neurodegenerative processes in ApoE-/-mice. Consequently, this study supports previous observations showing that metformin causes impairment of cognition.

Transgenic animal models of Aβ pathology provide mechanistic insight into some aspects of Alzheimer disease (AD) pathology related to Aβ accumulation. Quantitative neuroimaging is a possible aid to improve translation of mechanistic findings in transgenic models to human end phenotypes of brain morphology or function. Therefore, we combined MRI-based morphometry, MRS-based NAA-assessment and quantitative histology of neurons and amyloid plaque load in the APPswe/PS1dE9 mouse model to determine the interrelationship between morphological changes, changes in neuron numbers and amyloid plaque load with reductions of NAA levels as marker of neuronal functional viability. The APPswe/PS1dE9 mouse showed an increase of Aβ plaques, loss of neurons and an impairment of NAA/Cr ratio, which however was not accompanied with brain atrophy. As brain atrophy is one main characteristic in human AD, conclusions from murine to human AD pathology should be drawn with caution.

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [¹⁸F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [¹⁸F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [¹⁸F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [¹⁸F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [¹⁸F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [¹⁸F]-florbetaben in the APPswe/PS1dE9 mouse model.

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.