The Role of Neuronal Insulin/Insulin-Like Growth Factor-1 Signaling for the Pathogenesis of Alzheimer’s Disease: Possible Therapeutic Implications
Johanna Zemva and Markus Schubert
Affiliation: SCIVIAS Hospital St. Josef, Internal Medicine, Eibinger Str. 9, 65385 Rudesheim am Rhein, Germany.
Recent data suggest that brains of patients with Alzheimer’s disease (AD) are insulin and insulin-like growth
factor-1 (IGF-1) resistant. So far, there have been two different approaches to investigate possible therapeutic implications
of modulating cerebral insulin/IGF-1 signaling (IIS) in AD. One approach is peripheral or intranasal administration of
insulin or IGF-1. Intranasal and peripheral insulin administration has been shown to improve memory in patients with AD.
Additionally, peripheral IGF-1 administration resulted in decreased amyloid-beta (Aβ) levels in brains of AD mouse
models accompanied by elevated Aβ levels in the cerebrospinal fluid (CSF). Insulin and IGF-1 regulate multicargotransporters
influencing trafficking of several molecules including Aβ from the brain to the blood as well as to the CSF
and possibly vice versa. Furthermore, insulin and related peptides regulate neurovascular coupling changing regional
blood flow. Thus, positive effects of peripheral insulin/IGF-1 administration on AD pathology might be due to changes in
the blood-brain-barrier (BBB) and/or in the transport between the CSF/blood and the brain. Clinical and experimental data
suggest that increased serum insulin and IGF-1 levels do not necessarily correlate with an upregulation of neuronal
insulin/IGF-1 receptor signaling. Therefore, the second approach in investigating the role of neuronal IIS for the
pathogenesis of AD analyzes knockout mice lacking components of the IIS in AD models. Haploinsufficiency of the IGF-
1 receptor (IGF-1R) (IGF-1R+/- mice) as well as neuronal deficiency of the insulin receptor (IR) (nIR-/- mice) or IGF-1R
(nIGF-1R-/- mice) leads to delayed Aβ accumulation when crossed with mouse models for AD. Furthermore, insulin
receptor substrate (IRS)-2 knockout mice (IRS-2-/- mice) show reduced Aβ levels in an Alzheimer background. These data
suggest beneficial effects of decreased neuronal IIS on Alzheimer-pathology and question the therapeutic outcome of
long-term administration of insulin or IGF-1 in patients with AD. Whether the observed phenomenon of cerebral insulin
and IGF-1 resistance even at an early stage of Alzheimer's disease is cause, consequence or possibly counter-regulation to
AD-pathology needs further investigation and should lead to critical discussions. The current review discusses the pros
and cons of targeting insulin/IGF-1 signaling as therapeutic approach for AD.
Keywords: Amyloid, Alzheimer’s disease, diabetes mellitus, insulin-like growth factor-1 receptor, insulin receptor, insulin
receptor substrates, tau.
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