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

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.

Inulin supplementation prior to mild traumatic brain injury mitigates gut dysbiosis, and brain vascular and white matter deficits in mice

“…It is well documented that TBI increases the risk for developing dementia, such as Alzheimer’s disease (AD) later in life Mortimer et al, 1991 ; Gavett et al, 2010 ; Lee et al, 2013 ; ( Barnes et al, 2016 ). Protecting brain vascular and metabolic functions ( Hammond et al, 2020 ; Hammond et al, 2021 ; Hammond and Lin, 2022 ) is critical to slowing down brain aging ( Hoffman et al, 2017 ) and mitigating the risk for AD ( Lee et al, 2018 ; Lin et al, 2020 ), as these functions serve an essential role in sustaining essential brain activities ( Lin et al, 2008 ; Lin et al, 2010 ). It is also consistent with our previous findings that inulin is protective of systemic metabolism and reduces the risk for AD in a mouse model with human APOE4 alleles, the strongest genetic risk factor for AD ( Hoffman et al, 2019 ; Yanckello et al, 2021 ).…”

Autophagy induction in the treatment of Alzheimer's disease

“…Rapamycin (sirolimus) enhances autophagy via the direct binding to mTOR and FKBP12, leading to the inhibition of mTORC1, and is the most studied agent in preclinical models of AD. Rapamycin was demonstrated to enhance Aβ degradation and to reduce plaque burden, to decrease the number of tau tangles, to ameliorate neuro‐inflammation, to restore brain vascular and metabolic functions and to reverse cognitive deficits in numerous in vitro and in vivo AD settings (Lee, Yanckello, et al, ; Pierzynowska et al, ). Other agents that inhibit mTORC1 in a manner similar to rapamycin (rapalogs) also displayed protective properties in the context of AD; For example, temsirolimus promoted clearance of amyloid‐β and provided protective effects in cellular and animal models of AD (Jiang et al, ); and administration of everolimus restored cognitive function and mood in a murine model of AD (Cassano et al, ).…”

Caloric Restriction (CR) Plus High-Nitrate Beetroot Juice Does Not Amplify CR-Induced Metabolic Adaptation and Improves Vascular and Cognitive Functions in Overweight Adults: A 14-Day Pilot Randomised Trial

“…Justice et al [ 72 ] showed a similar result in healthy older subjects as time to complete TMT-B was improved by 18% and 14% in response to supplementation with high and low doses of sodium nitrite for 10 weeks, respectively. Potential mechanisms explaining the cognitive effects could include a CR-induced Akt phosphorylation through the insulin-PI3K-Akt signalling pathway [ 73 , 74 ], increased NO production, and potentiation of pre-synaptic neurotransmission [ 75 , 76 ] occurring alongside an enhancement of neurovascular and metabolic coupling [ 77 ].…”