Geroprotective interventions in the 3xTg mouse model of Alzheimer’s disease

Sonsalla, Michelle; Lamming, Dudley W.

doi:10.1007/s11357-023-00782-w

Cited by 10 publications

(7 citation statements)

References 352 publications

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“…While phosphorylation of these substrates acts to promote macromolecule synthesis, mTORC1 activity acts as a key negative break on autophagy, via the phosphorylation of ULK1 39,40 ; consequently, increased mTORC1 activity accelerates the production of Aβ and accumulation of tau 38,41 . Furthermore, treatment with rapamycin, a drug which inhibits mTORC1 activity, slows or prevents AD in multiple mouse models of AD, and genetic depletion of S6K1, a substrate and effector of mTORC1, is sufficient to improve memory and reduce AD pathology in 3xTg mice 38,[42][43][44] .…”

Section: Introductionmentioning

confidence: 99%

“…The 3xTg mouse model, expresses familial human isoforms of APP (APPSwe), Tau(tauP301L), and Presenilin (PS1M146V), and exhibits both Aβ and tau pathology 47 , as well as cognitive deficits 48,49 . Further, the 3xTg model has been used to examine the effect of many different geroprotective interventions on AD 44 . Here, we fed 3xTg mice as well as non-transgenic (NTg) controls either a Control diet (21% protein) or a PR diet (7% protein) starting at 6 months of age, which is after the age at which 3xTg mice develop cognitive deficits and have intracellular Aβ immunoreactivity in parts of the hippocampus and cortex 50 .…”

Section: Introductionmentioning

confidence: 99%

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Protein restriction slows the development and progression of Alzheimer's disease in mice

Babygirija,

Sonsalla,

Han

et al. 2023

Preprint

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Over the last decade, it has become evident that dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and we and others have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer’s disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice. We found that PR induces sex-specific alterations in circulating metabolites and in the brain lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein restriction slows the development and progression of Alzheimer's disease in mice

Babygirija,

Sonsalla,

Han

et al. 2023

Preprint

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“…38 It is a well-characterized and extensively phenotyped model of AD pathogenesis, 39 and has been successfully utilized as a pre-clinical and drug discovery platform in the past. [40][41][42] Importantly, sexually dimorphic characteristics are becoming a well-recognized feature of this transgenic model, although their prevalence and impact on AD-associated pathological hallmarks such as inflammation, plaque, and/or tangle accumulation and others remain poorly understood (reviewed in 43 ). Therefore, we sequenced the hippocampus from female 3xTg-AD and wild-type (WT) littermates at 6 and 12 months (Fig 1A) to evaluate altered glia-neuron communication.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Soelter,

Howton,

Wilk

et al. 2024

Preprint

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Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-β ; plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cell-cell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice.

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“…While phosphorylation of these substrates acts to promote macromolecule synthesis, mTORC1 activity acts as a key negative break on autophagy, via the phosphorylation of ULK1 40,41 ; consequently, increased mTORC1 activity accelerates the production of A and accumulation of tau 39,42 . Furthermore, treatment with rapamycin, a drug which inhibits mTORC1 activity, slows or prevents AD in multiple mouse models of AD, and genetic depletion of S6K1, a substrate and effector of mTORC1, is sufficient to improve memory and reduce AD pathology in 3xTg mice 39,[43][44][45] .…”

Section: Introductionmentioning

confidence: 99%

“…However, over the past two decades, phenotypic drifts have occurred, and recent studies have found a later onset of AD pathology as well as sex differences 52 . The 3xTg model has been used to examine the effect of many different interventions on AD 45 and since this model exhibits both plaque and tau pathology we considered this as an ideal model to investigate the effects of dietary interventions. Here, we fed 3xTg mice as well as non-transgenic (NTg) controls either a Control diet (21% protein) or a PR diet (7% protein) starting at 6 months of age, which is after the age at which 3xTg mice develop cognitive deficits and have intracellular Aβ immunoreactivity in parts of the hippocampus and cortex 53 .…”

Section: Introductionmentioning

confidence: 99%

Protein restriction slows the development and progression of Alzheimer's disease in mice

Babygirija,

Sonsalla,

Mill

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer’s disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain metabolome and lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

show abstract

Geroprotective interventions in the 3xTg mouse model of Alzheimer’s disease

Cited by 10 publications

References 352 publications

Protein restriction slows the development and progression of Alzheimer's disease in mice

Protein restriction slows the development and progression of Alzheimer's disease in mice

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Protein restriction slows the development and progression of Alzheimer's disease in mice

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