Dataset Information

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice.

ABSTRACT: Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces ?-amyloid (A?) production and plaque formation after 6 weeks of treatment in 4.5-month-old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c-Jun N-terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in A? metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on A? pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

SUBMITTER: Mao YF

PROVIDER: S-EPMC5013027 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice.

Mao Yan-Fang YF Guo Zhangyu Z Zheng Tingting T Jiang Yasi Y Yan Yaping Y Yin Xinzhen X Chen Yanxing Y Zhang Baorong B

Aging cell 20160726 5

Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β-amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5-month-old APPswe/PS1dE9 (APP/PS1) mice. Furthe ...[more]

PMID: 27457264

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Project description:Brain-derived neurotrophic factor (BDNF) importantly regulates learning and memory and supports the survival of injured neurons. Reduced BDNF levels have been detected in the brains of Alzheimer's disease (AD) patients but the exact role of BDNF in the pathophysiology of the disorder remains obscure. We have recently shown that reduced signaling of BDNF receptor TrkB aggravates memory impairment in APPswe/PS1dE9 (APdE9) mice, a model of AD. The present study examined the influence of Bdnf gene deficiency (heterozygous knockout) on spatial learning, spontaneous exploratory activity and motor coordination/balance in middle-aged male and female APdE9 mice. We also studied brain BDNF protein levels in APdE9 mice in different ages showing progressive amyloid pathology. Both APdE9 and Bdnf mutations impaired spatial learning in males and showed a similar trend in females. Importantly, the effect was additive, so that double mutant mice performed the worst. However, APdE9 and Bdnf mutations influenced spontaneous locomotion in contrasting ways, such that locomotor hyperactivity observed in APdE9 mice was normalized by Bdnf deficiency. Obesity associated with Bdnf deficiency did not account for the reduced hyperactivity in double mutant mice. Bdnf deficiency did not alter amyloid plaque formation in APdE9 mice. Before plaque formation (3 months), BDNF protein levels where either reduced (female) or unaltered (male) in the APdE9 mouse cortex. Unexpectedly, this was followed by an age-dependent increase in mature BDNF protein. Bdnf mRNA and phospho-TrkB levels remained unaltered in the cortical tissue samples of middle-aged APdE9 mice. Immunohistological studies revealed increased BDNF immunoreactivity around amyloid plaques indicating that the plaques may sequester BDNF protein and prevent it from activating TrkB. If similar BDNF accumulation happens in human AD brains, it would suggest that functional BDNF levels in the AD brains are even lower than reported, which could partially contribute to learning and memory problems of AD patients.

Dataset Information

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice.

Publications

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice.

Similar Datasets

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