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Insulin receptor expression and activity in the brains of nondiabetic sporadic Alzheimer's disease cases.

Ho L, Yemul S, Knable L, Katsel P, Zhao R, Haroutunian V, Pasinetti GM - Int J Alzheimers Dis (2012)

Bottom Line: We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases.Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/β in brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia.Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY 10029, USA.

ABSTRACT
We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβ as surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer's disease (AD) cases. We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases. Moreover, total IRβ and [Tyr1162/1163]-phosphorylated IRβ levels in the hippocampal formation are not correlated with the severity of amyloid or tau-neuropathology. Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/β in brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia. Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.

No MeSH data available.


Related in: MedlinePlus

Total IRβ and [Tyr1162/1163]-phosphorylated IRβ contents in the brain are not correlated with the severity of AD-type neuropathology. AD-type neuritic plaque (NP) and neurofibrillary tangle (NFT) neuropathology were assessed using CERAD rating scales. In ((a) and (c)), correlation analysis of total IRβ content with NP (a) and NFT (c) neuropathology in the brain. In ((b) and (d)), correlation analysis of [Tyr1162/1163]-phosphorylated IRβ contents with NP (b) and NFT (d) neuropathology. In ((a)–(d)), solid line represents the best-fit correlation between IRβ or [Tyr1162/1163]-phosphorylated IRβ with NP or NFT neuropathology. Pearson correlation analysis; P = .749 and  .516 for IRβ contents with NP and NFT neuropathology, respectively; P = .283 and  .912 for [Tyr1162/1163]-phosphorylated IRβ contents with NP and NFT neuropathology, respectively.
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fig4: Total IRβ and [Tyr1162/1163]-phosphorylated IRβ contents in the brain are not correlated with the severity of AD-type neuropathology. AD-type neuritic plaque (NP) and neurofibrillary tangle (NFT) neuropathology were assessed using CERAD rating scales. In ((a) and (c)), correlation analysis of total IRβ content with NP (a) and NFT (c) neuropathology in the brain. In ((b) and (d)), correlation analysis of [Tyr1162/1163]-phosphorylated IRβ contents with NP (b) and NFT (d) neuropathology. In ((a)–(d)), solid line represents the best-fit correlation between IRβ or [Tyr1162/1163]-phosphorylated IRβ with NP or NFT neuropathology. Pearson correlation analysis; P = .749 and  .516 for IRβ contents with NP and NFT neuropathology, respectively; P = .283 and  .912 for [Tyr1162/1163]-phosphorylated IRβ contents with NP and NFT neuropathology, respectively.

Mentions: Consistent with our observation that AD-dementia in nondiabetic cases is not associated with significant changes in the contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ in the brain (Figures 2(c)-2(d)), we found that total or [Tyr1162/1163]-phosphorylated IRβ contents are not correlated with AD-type amyloid neuritic plaque (NP) or neurofibrillary tangle (NFT) neuropathology in the brain (Figures 4(a)–4(d)). In particular, based on histological assessments of neuritic plaques and neurofibrillary tangles using the 4-point CERAD rating, we found no correlation between the content of total IRβ in the hippocampal formation and either NPs (Figure 4(a); P = .749) or NFTs (Figure 4(c); P = .516). Similarly, we found no correlation between the contents of [Tyr1162/1163]-phosphorylated IRβ in the hippocampal formation and either NPs (Figure 4(b); P = .283) or NFTs (Figure 4(d); P = .912).


Insulin receptor expression and activity in the brains of nondiabetic sporadic Alzheimer's disease cases.

Ho L, Yemul S, Knable L, Katsel P, Zhao R, Haroutunian V, Pasinetti GM - Int J Alzheimers Dis (2012)

Total IRβ and [Tyr1162/1163]-phosphorylated IRβ contents in the brain are not correlated with the severity of AD-type neuropathology. AD-type neuritic plaque (NP) and neurofibrillary tangle (NFT) neuropathology were assessed using CERAD rating scales. In ((a) and (c)), correlation analysis of total IRβ content with NP (a) and NFT (c) neuropathology in the brain. In ((b) and (d)), correlation analysis of [Tyr1162/1163]-phosphorylated IRβ contents with NP (b) and NFT (d) neuropathology. In ((a)–(d)), solid line represents the best-fit correlation between IRβ or [Tyr1162/1163]-phosphorylated IRβ with NP or NFT neuropathology. Pearson correlation analysis; P = .749 and  .516 for IRβ contents with NP and NFT neuropathology, respectively; P = .283 and  .912 for [Tyr1162/1163]-phosphorylated IRβ contents with NP and NFT neuropathology, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
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fig4: Total IRβ and [Tyr1162/1163]-phosphorylated IRβ contents in the brain are not correlated with the severity of AD-type neuropathology. AD-type neuritic plaque (NP) and neurofibrillary tangle (NFT) neuropathology were assessed using CERAD rating scales. In ((a) and (c)), correlation analysis of total IRβ content with NP (a) and NFT (c) neuropathology in the brain. In ((b) and (d)), correlation analysis of [Tyr1162/1163]-phosphorylated IRβ contents with NP (b) and NFT (d) neuropathology. In ((a)–(d)), solid line represents the best-fit correlation between IRβ or [Tyr1162/1163]-phosphorylated IRβ with NP or NFT neuropathology. Pearson correlation analysis; P = .749 and  .516 for IRβ contents with NP and NFT neuropathology, respectively; P = .283 and  .912 for [Tyr1162/1163]-phosphorylated IRβ contents with NP and NFT neuropathology, respectively.
Mentions: Consistent with our observation that AD-dementia in nondiabetic cases is not associated with significant changes in the contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ in the brain (Figures 2(c)-2(d)), we found that total or [Tyr1162/1163]-phosphorylated IRβ contents are not correlated with AD-type amyloid neuritic plaque (NP) or neurofibrillary tangle (NFT) neuropathology in the brain (Figures 4(a)–4(d)). In particular, based on histological assessments of neuritic plaques and neurofibrillary tangles using the 4-point CERAD rating, we found no correlation between the content of total IRβ in the hippocampal formation and either NPs (Figure 4(a); P = .749) or NFTs (Figure 4(c); P = .516). Similarly, we found no correlation between the contents of [Tyr1162/1163]-phosphorylated IRβ in the hippocampal formation and either NPs (Figure 4(b); P = .283) or NFTs (Figure 4(d); P = .912).

Bottom Line: We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases.Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/β in brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia.Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY 10029, USA.

ABSTRACT
We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβ as surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer's disease (AD) cases. We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases. Moreover, total IRβ and [Tyr1162/1163]-phosphorylated IRβ levels in the hippocampal formation are not correlated with the severity of amyloid or tau-neuropathology. Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/β in brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia. Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.

No MeSH data available.


Related in: MedlinePlus