While a potential causal factor in Alzheimer’s disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS616) and IRS-1 pS636/639. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS616 and IRS-1 pS636/639 and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.
Konrad Talbot, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P. Bakshi, Andres Stucky, Robert L. Fuino, Krista R. Kawaguchi, Andrew J. Samoyedny, Robert S. Wilson, Zoe Arvanitakis, Julie A. Schneider, Bryan A. Wolf, David A. Bennett, John Q. Trojanowski, Steven E. Arnold
Submitter: R.S. Anand | email@example.com
Centre for Biotechnology, Anna University
Published October 22, 2013
Understanding the molecular mechanism of Alzheimer’s disease (AD) is of great importance in developing therapeutic strategies towards it. The work by Talbot et al., (2012) in The Journal of Clinical Investigation is a step closer to this realization in AD. But I have a slightly alternative perspective from that presented in their work. The set of data that led me to this perspective is as follows
1. In the Supplemental Table 2, it is given that the levels of tyrosine 960 phosphorylated Insulin receptor levels at 0 nM insulin (basal levels) in Normal patients is 0.16 ± 0.02 whereas in Alzheimer’s patients it is 0.20 ± 0.03 in cerebellar cortex. This shows that there must be a presence of hyper-insulin signaling in vivo.
2. The above trend applies the same to all sites of IRS1 phosphorylation, also in the same table.
3. In Supplemental Table 3A also the levels of IRS1 tyrosine 612 phosphorylation is higher (0.24 ± 0.02) in the hippocampal formation of AD patients than in control (0.10 ± 0.01) at 0 nM insulin. Moreover, it can be seen that with stimulation with 1 nM insulin the levels are same between AD and control (~0.30) while it decreases in AD tissues only at 10 nM insulin to 0.32 ± 0.01 compared to 0.41 ± 0.02 in normal tissues.
4. Supplemental Table 3B shows that the levels of AKT 473 phosphorylation, an hall mark of insulin signaling, at 0 nM insulin is also high in the hippocampal formation of AD patients (0.34 ± 0.02) when compared to normal (0.11 ± 0.02). This trend also extends to GSK-3 beta serine 9 phosphorylation, mTOR serine 2448 phosphorylation and ERK2 Threonine 185/Tyrosine 187 phosphorylation thus confirming the presence of hyper-insulin signaling. The same argument can be extended to the IGF stimulated phosphorylation at 0 nM insulin given in Supplemental Table 4 and 5.
5. In summary the basal levels (0 nM insulin/IGF treatment) of insulin signaling activation state in AD tissues are higher than that of controls supporting that there might exist hyper-insulin signaling at a threshold state which tends to show insulin resistance due to feedback inhibition on exogenous insulin stimulation (possibly through receptor internalization).
6. One possible support to this view comes from the work of Romanelli et al., (2007) wherein they show that at 30 min (which is also the insulin/IGF treatment time in the study by Talbot et al., (2012)) after 1 nM IGF treatment the receptor levels in the cell surface are decreased due to receptor internalization (Figure 5A and B of Romanelli et al., 2007)
The view that there is a presence of hyper-insulin signaling in the tissues rather than insulin resistance under basal conditions could be extrapolated to the actual treatments in AD patients that are targeted to decrease the hyper-insulin signaling rather than treating with drugs to further stimulate the insulin signaling (thinking that the tissues are in insulin resistant state) which would obviously lead to insulin resistance as found in the study by Talbot et al., (2012).
Thus my perspective from the work by Talbot et al., (2012) is that Alzheimers disease pathology is associated with hyper-insulin signaling in vivo and it tends to show features of Insulin resistance on further stimulation with insulin/IGF in vitro.
Talbot et al., Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline (2012) Journal of Clinical Investigation, 122(4), 1316–1338.
Romanelli et al., Insulin-like Growth Factor Type-I Receptor Internalization and Recycling Mediate the Sustained Phosphorylation of Akt (2007) Journal of Biological Chemistry, 282, 22513-22524
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