Regional hypometabolism in the 3xTg mouse model of Alzheimer's disease

Adlimoghaddam, Aida; Snow, Wanda M.; Stortz, Greg; Pérez, Claudia; Djordjević, Jelena; Goertzen, Andrew L.; Ko, Ji Hyun; Albensi, Benedict C.

doi:10.1016/j.nbd.2019.03.008

Cited by 44 publications

(35 citation statements)

References 130 publications

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“…These findings also have important implications for AD treatment as demonstrated by recent studies by Snow et al (2018) and as shown in other related studies (Djordjevic et al, 2017; Adlimoghaddam et al, 2019) that suggest targeting NF-κB signaling in the mitochondria may have therapeutic value. For example, in Snow et al’s study, creatine – a known modulator of mitochondrial function (Tarnopolsky and Beal, 2001), was shown to increase and positively alter protein levels of CaMKII, PSD-95, and Complex 1 subunits in creatine fed mice, whereas the NF-κB inhibitory IκB subunit was decreased.…”

Section: Nf-κb Mediates Aβ-induced Dysfunction In the Mitochondriasupporting

confidence: 70%

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?

Albensi

2019

Front. Cell Dev. Biol.

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A large body of literature supports the idea that nuclear factor kappa B (NF-κB) signaling contributes to not only immunity, but also inflammation, cancer, and nervous system function. However, studies on NF-κB activity in mitochondrial function are much more limited and scattered throughout the literature. For example, in 2001 it was first published that NF-κB subunits were found in the mitochondria, including not only IkBα and NF-κB p65 subunits, but also NF-κB pathway proteins such as IKKα, IKKβ, and IKKγ, but not much follow-up work has been done to date. Upon further thought the lack of studies on NF-κB activity in mitochondrial function is surprising given the importance and the evolutionary history of both NF-κB and the mitochondrion. Both are ancient in their appearance in our biological record where both contribute substantially to cell survival, cell death, and the regulation of function and/or disease. Studies also show NF-κB can influence mitochondrial function from outside the mitochondria. Therefore, it is essential to understand the complexity of these roles both inside and out of this organelle. In this review, an attempt is made to understand how NF-κB activity contributes to overall mitochondrial function – both inside and out. The discussion at times is speculative and perhaps even provocative to some, since NF-κB does not yet have defined mitochondrial targeting sequences for some nuclear-encoded mitochondrial genes and mechanisms of mitochondrial import for NF-κB are not yet entirely understood. Also, the data associated with the mitochondrial localization of proteins must be yet further proved with additional experiments.

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Section: Nf-κb Mediates Aβ-induced Dysfunction In the Mitochondriasupporting

confidence: 70%

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?

Albensi

2019

Front. Cell Dev. Biol.

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283

175

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“…Mitochondrial anomalies occur early in disease progression [ 4 ], with individuals displaying early metabolic changes (impaired glucose metabolism, mitochondrial dysfunction, and altered energy homeostasis) prior to the emergence of any histopathological or clinical abnormalities. Our previous studies showed early changes in mitochondrial membrane potential and oxygen consumption rates in the cortex [ 11 ], and impaired brain metabolic activity in adult 3xTg male mice, as measured with FDG-PET [ 12 ]. Importantly, these bioenergetic changes were found in the absence of excess amyloid-β (Aβ) plaque deposition in the brain, a neuropathological hallmark of the disease, suggesting that brain hypometabolism occurs prior to AD pathology.…”

Section: Introductionmentioning

confidence: 99%

Early Onset of Sex-Dependent Mitochondrial Deficits in the Cortex of 3xTg Alzheimer’s Mice

Djordjević

Chowdhury

Snow

et al. 2020

Cells

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Alzheimer’s disease (AD) is a major public health concern worldwide. Advanced age and female sex are two of the most prominent risk factors for AD. AD is characterized by progressive neuronal loss, especially in the cortex and hippocampus, and mitochondrial dysfunction has been proposed to be an early event in the onset and progression of the disease. Our results showed early perturbations in mitochondrial function in 3xTg mouse brain, with the cortex being more susceptible to mitochondrial changes than the hippocampus. In the cortex of 3xTg females, decreased coupled and uncoupled respiration were evident early (at 2 months of age), while in males it appeared later at 6 months of age. We observed increased coupled respiration in the hippocampus of 2-month-old 3xTg females, but no changes were detected later in life. Changes in mitochondrial dynamics were indicated by decreased mitofusin (Mfn2) and increased dynamin related protein 1 (Drp1) (only in females) in the hippocampus and cortex of 3xTg mice. Our findings highlight the importance of controlling and accounting for sex, brain region, and age in studies examining brain bioenergetics using this common AD model in order to more accurately evaluate potential therapies and improve the sex-specific translatability of preclinical findings.

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“…human diseases, cardiovascular, neurodegenerative, and cancers, which may serve as an important and primary therapeutic target [4][5][6][7][8][9]. Low doses of the anti-cancer drug nilotinib suggest cognitive benefits for patients with Parkinson's disease (PD) and related dementias [10,11].…”

mentioning

confidence: 99%

“…The notion of testing nilotinib for AD may seem counterintuitive since AD involves cell loss and cancer involves unregulated cell proliferation, but the earliest deficits in the pathological progression of AD and cancer are associated with mitochondrial dysfunction; that is, before the robust appearance of neurotoxic proteins in AD and oncogene expression in cancer [4][5][6][7][8][32][33][34][35][36][37][38][39].…”

mentioning

confidence: 99%

“…Previously, our laboratory documented reductions in brain metabolic activity and in the expression of mitochondrial protein subunits (Complexes I-V) in 3xTg brain samples estimated to compromise the site of oxidative phosphorylation (OXPHOS) and mitochondrial efficiency through the action of ATP synthesis [8]. Beside down-regulation of OXPHOS capacity in AD, reduced activity of other mitochondrial metabolic enzymes such as citrate synthase (CS) is associated with AD [46].…”

mentioning

confidence: 99%

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Nilotinib Improves Bioenergetic Profiling in Brain Astroglia in the 3xTg Mouse Model of Alzheimer’s Disease

Adlimoghaddam¹,

Odero²,

Glazner³

et al. 2021

Aging and disease

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Current treatments targeting amyloid beta in Alzheimer's disease (AD) have minimal efficacy, which results in a huge unmet medical need worldwide. Accumulating data suggest that brain mitochondrial dysfunction play a critical role in AD pathogenesis. Targeting cellular mechanisms associated with mitochondrial dysfunction in AD create a novel approach for drug development. This study investigated the effects of nilotinib, as a selective tyrosine kinase inhibitor, in astroglia derived from 3xTg-AD mice versus their C57BL/6-controls. Parameters included oxygen consumption rates (OCR), ATP, cytochrome c oxidase (COX), citrate synthase (CS) activity, alterations in oxidative phosphorylation (OXPHOS), nuclear factor kappa B (NF-κB), key regulators of mitochondrial dynamics (mitofusin (Mfn1), dynamin-related protein 1 (Drp1)), and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α), calcium/calmodulindependent protein kinase II (CaMKII), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)). Nilotinib increased OCR, ATP, COX, Mfn1, and OXPHOS levels in 3xTg astroglia. No significant differences were detected in levels of Drp1 protein and CS activity. Nilotinib enhanced mitochondrial numbers, potentially through a CaMKII-PGC1α-Nrf2 pathway in 3xTg astroglia. Additionally, nilotinib-induced OCR increases were reduced in the presence of the NF-κB inhibitor, Bay11-7082. The data suggest that NF-κB signaling is intimately involved in nilotinib-induced changes in bioenergetics in 3xTg brain astroglia. Nilotinib increased translocation of the NF-κB p50 subunit into the nucleus of 3xTg astroglia that correlates with an increased expression and activation of NF-κB. The current findings support a role for nilotinib in improving mitochondrial function and suggest that astroglia may be a key therapeutic target in treating AD.

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Regional hypometabolism in the 3xTg mouse model of Alzheimer's disease

Cited by 44 publications

References 130 publications

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?

Early Onset of Sex-Dependent Mitochondrial Deficits in the Cortex of 3xTg Alzheimer’s Mice

Nilotinib Improves Bioenergetic Profiling in Brain Astroglia in the 3xTg Mouse Model of Alzheimer’s Disease

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