The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer’s Disease
Introduction
Insulin signaling and longevity. Insulin signaling through insulin and insulin-like growth factors (IGFs) has evolved to represent the metabolic code which couples size and growth rates to the nutrient environment or food chain. Interspecies correlative data associate longevity with slow growth rates, large size, low predation and delayed reproduction, while shorter lifespans were associated with tumor promotion and mitogenic signaling for rapid growth for animals at the bottom of the food chain. Thus, in general, heavily predated smaller species that have adapted by R-selection for rapid growth and maturation have higher metabolic rates, fuel demands and shorter life spans than larger species closer to the top of the food chain that have evolved by K-selection for adaptation to the environmental carrying capacity. Insulin signaling appears integral to scale lifespan to the environmental niche. Thus, in recent years the familiar role of insulin in glucose regulation and diabetes has been extended beyond metabolism to mechanisms controlling aging rates, including caloric restriction. Consistent with the evolutionary perspective, insulin/IGF1 receptor signaling has been implicated as an important factor in invertebrate and vertebrate development, nutrient sensing, growth and aging (Hafen, 2004, Bartke, 2006). For example, scarce food and caloric restriction in the nematode Caenorhabditis elegans results in adaptive insulin signaling-dependent developmental arrest and long-lived dauer larvae. Genetic dissection of the dauer phenotype has identified a series of genes with mammalian homologues in the insulin signaling pathway (see below) that regulate invertebrate longevity beyond the dauer phenotype (e.g. Daf-2) (insulin/IGF-1 receptor), Age-1 (PI3-K), Daf-16 (FOXO), Daf-18 (PTEN), etc. Thus, partial loss of function in Daf genes leads to as much as a 3-fold increase in adult lifespan that is entirely dependent on Daf-16 (FOXO), a regulator of the cellular stress response. Insulin pathway mutations also influence aging in mice where defects limiting signaling through IGF receptor 1 result in long-lived mice with increased resistance to oxidative stress (Holzenberger et al., 2004). It is easy to imagine that limited mitogenesis and slowed growth rates would also reduce tumor promotion. Further, because aging can be viewed as increased mortality from diminished resistance to physiological and cellular stress, insulin-like signaling, which plays an important role in the cellular stress response, would be suitably positioned to play a central role in governing aging rates.
While these and other data implicate increased insulin/IGF-1 signaling as a key negative regulator of lifespan, insulin/IGF-1 signaling also overlaps neurotrophin survival signaling that plays a significant positive role in the brain. This presents a small puzzle with seemingly opposing impacts. Our objective here is to explore the relationship of insulin-like signaling to pathology and diet that modulates insulin or trophic factor resistance and how this relationship impacts brain aging and Alzheimer’s Disease risk.
Section snippets
Insulin signaling
The insulin receptor is a heterotetrameric tyrosine kinase receptor which, upon binding of insulin, undergoes dimerization and tyrosine autophosphorylation (see Fig. 1, readers unfamiliar with this literature may wish to refer to the GLOSSARY). Insulin binding activates the A subunit of the insulin receptor inducing a conformational change that leads to autophosphorylation of tyrosine residues in the B subunit; this allows recognition and further tyrosine phosphorylation of
Insulin signaling in the brain
Insulin is the prototypic trophic factor since trophic factor signaling overlaps the insulin pathways and is essential not only for neuronal development, but for continued survival in vitro and in vivo. In neurons, the ERK/MAPK and PI3-K> AKT> GSK3β, BAD, FOXO and TOR pathways are clearly critical for survival signaling, while regulation of glucose uptake is more problematic because in neurons it depends on GLUT3 rather than GLUT4. IGFs are potent neurotrophic agents (Carson et al., 1993) with
Alzheimer’s Disease (AD)
Alzheimer’s Disease (AD), a devastating neurodegenerative condition associated with impaired memory and cognitive function, is affecting an estimated 4.5 million people in the United States, the majority of whom are over 65 years old, posing a great economic burden with an estimated cost of $42,000 per year per person (Rice et al., 1993). AD is characterized by two pathological hallmarks: senile plaques that are composed mainly of aggregated fibrillar insoluble β-amyloid (Aβ), and
Diabetes
Recent prospective and retrospective epidemiological findings indicate that type II diabetes mellitus is a significant risk factor for developing AD (Ott et al., 1996, Leibson et al., 1997, Ott et al., 1999). Type II diabetes mellitus, a metabolic disorder affecting approximately 5% of Americans, is characterized by insulin resistance, increased insulin secretion and overt hyperglycemia (Olson and Norris, 2004). The enhanced risk for developing AD in diabetic patients remains strong even when
Amyloid peptides
Aβ aggregates can activate τ kinase 1 (GSK3β) (Takashima et al., 1993), an activity shared by Aβ oligomers which activate GSK3β in vitro and in vivo (Ma et al., 2006). GSK3β has many substrates, including IRS-1 which results in impaired insulin signaling (Eldar-Finkelman and Krebs, 1997). More recently, several groups have shown that pre-exposure of cultured neurons to soluble Aβ aggregates (oligomers) impairs the ERK response to NGF (Chromy et al., 2003) and the response to BDNF (Tong et al.,
Insulin
Acute treatment with a bolus of glucose known to stimulate insulin release (Craft et al., 1992) or insulin at 85 microU/ml can increase memory in AD patients. Craft and colleagues performed a dose-response trial with acute insulin treatment (with glucose clamped) on memory in AD patients and normal volunteers (Craft et al., 2003). Results again showed improved memory in non-ApoE4 AD patients at higher insulin doses (35 and 85 microU/ml), but improvements in ApoE4 patients only at lower doses (25
Acknowledgement
R01 AG13741, AT003008-01.
Glossary and Abbreviations
- Aβ
- Amyloid β-protein. 40–42 amino acid self-aggregating peptide implicated in AD
- AD
- Alzheimer’s disease. Age-related dementing disease with plaques and tangles
- AKT
- Protein kinase B (after AKT oncogene). Major “pro-survival” kinase
- AP-1
- Activator protein-1. A transcription factor
- ApoE
- Apolipoprotein E. Lipoprotein involved in cholesterol and Aβ transport. Allelic variant, ApoE4, is the major genetic risk factor for AD.
- APP
- Amyloid β-protein precursor, releases Aβ after cleavage by proteases (secretases)
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