In vivo alterations of mitochondrial activity and amyloidosis in early-stage senescence-accelerated mice: a positron emission tomography study

Satoru Yamagishi,Takeharu Kakiuchi,Yurika Iga,Kohji Sato,Daisuke Fukomoto,Shingo Nishiyama,Norihiro Harada,Masakatsu Kanazawa,Hiroyuki Ohba,Yasuomi Ouchi,Shunsuke Ikegaya,Hideo Tsukada

doi:10.1186/s12974-021-02343-4

Abstract

PurposeWhile marked reductions in neural activity and mitochondrial function have been reported in Alzheimer’s disease (AD), the degree of mitochondrial activity in mild cognitive impairment (MCI) or early-stage AD remains unexplored. Here, we used positron emission tomography (PET) to examine the direct relationship between mitochondrial activity (18F-BCPP-EF) and β-amyloid (Aβ) deposition (11C-PiB) in the same brains of senescence-accelerated mouse prone 10 (SAMP10) mice, an Aβ-developing neuroinflammatory animal model showing accelerated senescence with deterioration in cognitive functioning similar to that in MCI.MethodsFive- to 25-week-old SAMP10 and control SAMR1 mice, were used in the experiments. PET was used to measure the binding levels (standard uptake value ratios; SUVRs) of [18F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (18F-BCPP-EF) for mitochondrial complex 1 availability, and 11C-PiB for Aβ deposition, in the same animals, and immunohistochemistry for ATPB (an ATP synthase on the mitochondrial inner membrane) was also performed, to determine changes in mitochondrial activity in relation to amyloid burden during the early stage of cognitive impairment.ResultsThe SUVR of 18F-BCPP-EF was significantly lower and that of 11C-PiB was higher in the 15-week-old SAMP10 mice than in the control and 5-week-old SAMP10 mice. The two parameters were found to negatively correlate with each other. The immunohistochemical analysis demonstrated temporal upregulation of ATPB levels at 15-week-old, but decreased at 25 week-old SAMP10 mice.ConclusionThe present results provide in vivo evidence of a decrease in mitochondrial energy production and elevated amyloidosis at an early stage in SAMP10 mice. The inverse correlation between these two phenomena suggests a concurrent change in neuronal energy failure by Aβ-induced elevation of neuroinflammatory responses. Comparison of PET data with histological findings suggests that temporal increase of ATPB level may not be neurofunctionally implicated during neuropathological processes, including Aβ pathology, in an animal model of early-phase AD spectrum disorder.

Highlights

It is well recognized that mitochondrial dysfunction contributes to the neurodegeneration occurring in Alzheimer’s disease (AD)
positron emission tomography (PET) findings We first analyzed the mitochondrial activity in the brains of senescence-accelerated mouse resistant 1 (SAMR1) mice at 15 weeks of age and senescence-accelerated mouse prone 10 (SAMP10) mice at 5 and 15 weeks of age using 18F-BCPP-EF
In 15-week-old SAMP10 mice, the Standard uptake value ratios (SUVRs) was lower throughout the brain (Fig. 1C), being significantly lower than that of the 15-week-old SAMR1 mice (p = 0.0036, Fig. 2A), meaning that mitochondrial oxidative metabolism had decreased in the SAMP10 mice around the period of 15 weeks of age

Summary

Introduction

It is well recognized that mitochondrial dysfunction contributes to the neurodegeneration occurring in Alzheimer’s disease (AD). Recent findings suggest that pathological changes that occur in AD brains, such as synaptic and neuronal losses and excessive β-amyloid (Aβ) production, may be induced by mitochondrial dysfunction and increased oxidative stress [1]. In AD patients, mitochondria are reportedly characterized by impaired functioning, including lowered oxidative phosphorylation, decreased adenosine triphosphate production (ATP), increased generation of reactive oxygen species (ROS), and compromised antioxidant defense [2]. Mild cognitive impairment (MCI) is an intermediate condition of impaired cognitive function between normal aging and dementia, and is commonly associated with progression to AD [3, 4]. The Aβ deposition rate in patients with MCI who are likely to convert to AD is greater than that in stable patients [5]. The in vivo relationship between mitochondrial activity and Aβ level in the state of senescence to MCI remains unclear

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Discussion

Conclusion