Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

Velázquez, Ramón; Tran, An; Ishimwe, Egide; Denner, Larry; Dave, Nikhil; Oddo, Salvatore; Dineley, Kelly T.

doi:10.1016/j.neurobiolaging.2017.06.003

Cited by 73 publications

(72 citation statements)

References 99 publications

(167 reference statements)

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“…whether their brains becomes insensitive to insulin). On the one hand, Ho et al proposed that Tg2576 and 3xTg-AD models develop central insulin signaling dysregulation prior to peripheral insulin resistance [81]. In contrast, Stanley et al showed by direct central insulin delivery, that the brain from old APP/PS1 mice is still responsive to insulin even in the presence of aberrant amyloidosis [42].…”

Section: B) Central Insulin Resistance In T2dm and Ad Animal Modelsmentioning

confidence: 99%

Diabetes and Alzheimer’s Disease: A Link not as Simple as it Seems

Salas

Strooper

2018

Neurochem Res

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Section: B) Central Insulin Resistance In T2dm and Ad Animal Modelsmentioning

confidence: 99%

Diabetes and Alzheimer’s Disease: A Link not as Simple as it Seems

Salas

Strooper

2018

Neurochem Res

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“…Mouse proteins were prepared as previously described (Velazquez, Shaw, Caccamo & Oddo, 2016; Velazquez et al., 2017). One hemisphere of the brain was postfixed in 4% paraformaldehyde for 48 hr while the other hemisphere had the hippocampus and cortex isolated, flash‐frozen in dry ice, and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

et al. 2018

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SummaryMisfolded and hyperphosphorylated tau accumulates in several neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia with Parkinsonism, corticobasal degeneration, progressive supranuclear palsy, Down syndrome, and Pick's disease. Tau is a microtubule‐binding protein, and its role in microtubule stabilization is well defined. In contrast, while growing evidence suggests that tau is also involved in synaptic physiology, a complete assessment of tau function in the adult brain has been hampered by robust developmental compensation of other microtubule‐binding proteins in tau knockout mice. To circumvent these developmental compensations and assess the role of tau in the adult brain, we generated an adeno‐associated virus (AAV) expressing a doxycycline‐inducible short‐hairpin (Sh) RNA targeted to tau, herein referred to as AAV‐ShRNATau. We performed bilateral stereotaxic injections in 7‐month‐old C57Bl6/SJL wild‐type mice with either the AAV‐ShRNATau or a control AAV. We found that acute knockdown of tau in the adult hippocampus significantly impaired motor coordination and spatial memory. Blocking the expression of the AAV‐ShRNATau, thereby allowing tau levels to return to control levels, restored motor coordination and spatial memory. Mechanistically, the reduced tau levels were associated with lower BDNF levels, reduced levels of synaptic proteins associated with learning, and decreased spine density. We provide compelling evidence that tau is necessary for motor and cognitive function in the adult brain, thereby firmly supporting that tau loss‐of‐function may contribute to the clinical manifestations of many tauopathies. These findings have profound clinical implications given that anti‐tau therapies are in clinical trials for Alzheimer's disease.

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“…Dysregulations in insulin signaling have been reported in postmortem hippocampal and cortical samples from subjects with AD [86]. Another study observed an age-dependent progression in insulin signaling dysregulation that precedes peripheral insulin resistance in two preclinical AD models [87]. Hippocampal dysfunction and structural compromise are one of the early signs during AD onset [87-91].…”

Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 99%

“…Another study observed an age-dependent progression in insulin signaling dysregulation that precedes peripheral insulin resistance in two preclinical AD models [87]. Hippocampal dysfunction and structural compromise are one of the early signs during AD onset [87-91]. Insulin plays a very important role in AD progression by various complex mechanisms [92].…”

Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 99%

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Ahmad

Fatima

Mondal³

2019

Neuropsychobiology

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Alzheimer’s disease (AD), the commonest progressive neurodegenerative disorder of the brain, is clinically characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies suggest a relationship between the endocrinal dysregulation and the neuronal loss during the AD pathology. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis regulating circulating levels of glucocorticoid hormones has been implicated in the pathophysiology of AD. Likewise, dysregulated insulin signaling, impaired glucose uptake and insulin resistance are some of the prime factors in the onset/progression of AD. In this review, we have discussed the changes in HPA and HPG axes, implicated insulin resistance/signaling and glucose regulation during the onset/progression of AD. Therefore, simultaneous detection of these endocrinal markers in the early or presymptomatic stages may help in the early diagnosis of AD. This evidence for implicated endocrinal functions supports the fact that modulation of endocrinal pathways can be used as therapeutic targets for AD. Future studies need to determine how the induction or inhibition of endocrinal targets could be used for predictable neuroprotection in AD therapies.

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Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

Cited by 73 publications

References 99 publications

Diabetes and Alzheimer’s Disease: A Link not as Simple as it Seems

Diabetes and Alzheimer’s Disease: A Link not as Simple as it Seems

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

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