Neuroimaging Biomarkers of mTOR Inhibition on Vascular and Metabolic Functions in Aging Brain and Alzheimer's Disease.

Ishita Parikh,Anika M S Hartz,Bjoern Bauer,Lucille M Yanckello,Jared D Hoffman,Ai-Ling Lin,David Ma,Scott Thalman,Fahmeed Hyder,Jennifer Lee

doi:10.3389/fnagi.2018.00225

Ishita Parikh, Anika M S Hartz + Show 8 more

Open Access

https://doi.org/10.3389/fnagi.2018.00225

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Abstract

The mechanistic target of rapamycin (mTOR) is a nutrient sensor of eukaryotic cells. Inhibition of mechanistic mTOR signaling can increase life and health span in various species via interventions that include rapamycin and caloric restriction (CR). In the central nervous system, mTOR inhibition demonstrates neuroprotective patterns in aging and Alzheimer’s disease (AD) by preserving mitochondrial function and reducing amyloid beta retention. However, the effects of mTOR inhibition for in vivo brain physiology remain largely unknown. Here, we review recent findings of in vivo metabolic and vascular measures using non-invasive, multimodal neuroimaging methods in rodent models for brain aging and AD. Specifically, we focus on pharmacological treatment (e.g., rapamycin) for restoring brain functions in animals modeling human AD; nutritional interventions (e.g., CR and ketogenic diet) for enhancing brain vascular and metabolic functions in rodents at young age (5–6 months of age) and preserving those functions in aging (18–20 months of age). Various magnetic resonance (MR) methods [i.e., imaging (MRI), angiography (MRA), and spectroscopy (MRS)], confocal microscopic imaging, and positron emission tomography (PET) provided in vivo metabolic and vascular measures. We also discuss the translational potential of mTOR interventions. Since PET and various MR neuroimaging methods, as well as the different interventions (e.g., rapamycin, CR, and ketogenic diet) are also available for humans, these findings may have tremendous implications in future clinical trials of neurological disorders in aging populations.

Highlights

The mechanistic target of rapamycin is a nutrient sensor that mediates the responses to energy status and growth factor in eukaryotic cells (Laplante and Sabatini, 2009)
In a recent study (Lin et al, 2017a), we focused on the effects of rapamycin in presymptomatic mice carrying the human apolipoprotein ε4 (APOE4) allele, given that APOE4 is the most significant genetic risk factor for Alzheimer’s disease (AD) (Liu et al, 2013)
After 6 months of treatment, we found that rapamycin-treated APOE4 mice had normal cerebral blood flow (CBF) that was comparable to that of the sexand age-matched WT mice

Summary

INTRODUCTION

The mechanistic target of rapamycin (mTOR) is a nutrient sensor that mediates the responses to energy status and growth factor in eukaryotic cells (Laplante and Sabatini, 2009). Researchers conducting PET studies found that cognitively normal carriers of the APOE4 allele have abnormally low cerebral metabolic rates of glucose (CMRglc) in similar brain regions as patients diagnosed with AD (Reiman et al, 2001, 2004, 2005; Thambisetty et al, 2010; Fleisher et al, 2013). This metabolic abnormality was observed both in late-middle-aged (40–60 years of age) and young (20– 39 years of age) carriers, who have normal memory and cognitive ability and are without Aβ or tau pathology.

18 FDG Live-cell imaging

Findings

CONCLUSION