Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer’s disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-04-12

AUTHORS

Tomoko Wakabayashi, Kazuki Yamaguchi, Kentaro Matsui, Toshiharu Sano, Tetsuya Kubota, Tadafumi Hashimoto, Ayako Mano, Kaoru Yamada, Yuko Matsuo, Naoto Kubota, Takashi Kadowaki, Takeshi Iwatsubo

ABSTRACT

BackgroundBased on epidemiological and experimental studies, type 2 diabetes mellitus (T2DM), especially insulin resistance that comprises the core mechanism of T2DM, has been recognized as a significant risk factor for Alzheimer’s disease (AD). Studies in humans and diabetic AD model mice have indicated a correlation between insulin resistance and increased amyloid deposition in the brain. Paradoxically, mice with targeted disruption of genes involved in the insulin signaling pathway showed protective effects against the AD-related pathology. These conflicting observations raise an issue as to the relationship between dysregulation of insulin signaling and AD pathophysiology.MethodsTo study the causal relations and molecular mechanisms underlying insulin resistance-induced exacerbation of amyloid pathology, we investigated the chronological changes in the development of insulin resistance and amyloid pathology in two independent insulin-resistant AD mouse models, i.e., long-term high-fat diet (HFD) feeding and genetic disruption of Irs2, in combination with dietary interventions. In addition to biochemical and histopathological analyses, we examined the in vivo dynamics of brain amyloid-β (Aβ) and insulin by microdialysis technique.ResultsHFD-fed diabetic AD model mice displayed a reduced brain response to peripheral insulin stimulation and a decreased brain to plasma ratio of insulin during the hyperinsulinemic clamp. Diet-induced defective insulin action in the brain was accompanied by a decreased clearance of the extracellular Aβ in vivo and an exacerbation of brain amyloid pathology. These noxious effects of the HFD both on insulin sensitivity and on Aβ deposition in brains were reversibly attenuated by dietary interventions. Importantly, HFD feeding accelerated Aβ deposition also in the brains of IRS-2-deficient AD mice.ConclusionsOur results suggested a causal and reversible association of brain Aβ metabolism and amyloid pathology by diet-dependent, but not genetically-induced, insulin-resistance. These observations raise the possibility that the causal factors of insulin resistance, e.g., metabolic stress or inflammation induced by HFD feeding, but not impaired insulin signaling per se, might be directly involved in the acceleration of amyloid pathology in the brain. More... »

PAGES

15

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13024-019-0315-7

DOI

http://dx.doi.org/10.1186/s13024-019-0315-7

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https://app.dimensions.ai/details/publication/pub.1113377878

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30975165


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27 schema:description BackgroundBased on epidemiological and experimental studies, type 2 diabetes mellitus (T2DM), especially insulin resistance that comprises the core mechanism of T2DM, has been recognized as a significant risk factor for Alzheimer’s disease (AD). Studies in humans and diabetic AD model mice have indicated a correlation between insulin resistance and increased amyloid deposition in the brain. Paradoxically, mice with targeted disruption of genes involved in the insulin signaling pathway showed protective effects against the AD-related pathology. These conflicting observations raise an issue as to the relationship between dysregulation of insulin signaling and AD pathophysiology.MethodsTo study the causal relations and molecular mechanisms underlying insulin resistance-induced exacerbation of amyloid pathology, we investigated the chronological changes in the development of insulin resistance and amyloid pathology in two independent insulin-resistant AD mouse models, i.e., long-term high-fat diet (HFD) feeding and genetic disruption of Irs2, in combination with dietary interventions. In addition to biochemical and histopathological analyses, we examined the in vivo dynamics of brain amyloid-β (Aβ) and insulin by microdialysis technique.ResultsHFD-fed diabetic AD model mice displayed a reduced brain response to peripheral insulin stimulation and a decreased brain to plasma ratio of insulin during the hyperinsulinemic clamp. Diet-induced defective insulin action in the brain was accompanied by a decreased clearance of the extracellular Aβ in vivo and an exacerbation of brain amyloid pathology. These noxious effects of the HFD both on insulin sensitivity and on Aβ deposition in brains were reversibly attenuated by dietary interventions. Importantly, HFD feeding accelerated Aβ deposition also in the brains of IRS-2-deficient AD mice.ConclusionsOur results suggested a causal and reversible association of brain Aβ metabolism and amyloid pathology by diet-dependent, but not genetically-induced, insulin-resistance. These observations raise the possibility that the causal factors of insulin resistance, e.g., metabolic stress or inflammation induced by HFD feeding, but not impaired insulin signaling per se, might be directly involved in the acceleration of amyloid pathology in the brain.
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33 schema:keywords AD mice
34 AD model mice
35 AD mouse model
36 AD pathophysiology
37 AD-related pathology
38 Alzheimer's disease
39
40 Aβ deposition
41 Aβ metabolism
42 ConclusionsOur results
43 HFD
44 HFD feeding
45 IRS2
46 MethodsTo
47 ResultsHFD
48 T2DM
49 acceleration
50 action
51 addition
52 amyloid
53 amyloid deposition
54 amyloid pathology
55 analysis
56 association
57 brain
58 brain amyloid
59 brain amyloid pathology
60 brain insulin resistance
61 brain responses
62 causal
63 causal factors
64 causal relations
65 changes
66 chronological changes
67 clamp
68 clearance
69 combination
70 conflicting observations
71 core mechanism
72 correlation
73 decreased brain
74 decreased clearance
75 defective insulin action
76 deposition
77 development
78 diabetes mellitus
79 diet
80 diet feeding
81 dietary intervention
82 differential effects
83 disease
84 disruption
85 dynamics
86 dysregulation
87 effect
88 exacerbation
89 experimental study
90 extracellular Aβ
91 factors
92 feeding
93 genes
94 genetic disruption
95 high-fat diet feeding
96 histopathological analysis
97 humans
98 hyperinsulinemic clamp
99 inflammation
100 insulin
101 insulin action
102 insulin resistance
103 insulin sensitivity
104 insulin signaling
105 insulin stimulation
106 intervention
107 issues
108 long-term high-fat diet feeding
109 mechanism
110 mellitus
111 metabolic stress
112 metabolism
113 mice
114 microdialysis technique
115 model
116 model mice
117 molecular mechanisms
118 mouse model
119 noxious effects
120 observations
121 pathology
122 pathophysiology
123 pathway
124 possibility
125 protective effect
126 ratio
127 ratio of insulin
128 reduced brain response
129 relation
130 relationship
131 resistance
132 response
133 results
134 reversible association
135 risk factors
136 sensitivity
137 signaling
138 significant risk factors
139 stimulation
140 stress
141 study
142 targeted disruption
143 technique
144 type 2 diabetes mellitus
145 vivo
146 vivo dynamics
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