**5. IGF-1 in Alzheimer's disease**

Alzheimer's disease (AD) is a chronic and progressiv neurodegenerative disease and the most common form of dementia leading to the loss of cognitive abilities and finally to death (Citron 2002; Cole et al. 2007).

AD was first described by Alois Alzheimer, a German physician, in 1906 (Alzheimer et al. 1995). The disease is characterised by β-amyloid accumulation, formation of extracellular amyloid plaques as well as neurofibrillary tangles. The β-amyloid plaques mainly contain aggregated amyloid-β (Aβ) peptides (Masters et al. 1985). In contrast, the main components of neurofibrillary tangles are hyperphosphorylated and aggregated tau proteins (Ross et al., 2005). The aggregation of Aβ is thought to be the molecular basis of neurodegenration in AD (Masters et al. 1985).

#### **5.1 Tau**

The tau proteins consist of a N-terminal projection domain, a short tail sequence and a Cterminal domain with microtubule-binding (MTB) repeats. Six isoforms of tau are known in the human brain. These isoforms emerge from alternative splicing of exons 2, 3 and 10. Exon 2 and 3 encode N-terminal parts of tau and exon 10 codes for an additional MTB repeat. Thus, tau can present three or four MTB repeats (Ballatore, Lee, and Trojanowski 2007; Goedert and Spillantini 2006). Tau is predominantly located in the axons of neurons (Hirokawa et al. 1996) and is to less extend found in dendrites (Ittner et al. 2010). The function of tau is yet not completely understood, but it might influence the stabilisation of microtubules and regulation of axonal transport (Gotz, Ittner, and Kins 2006). Tau is phosporylated at several sites via kinases like glycogen synthase kinase 3 (GSK-3β), cyclin-dependent kinase 5 (Cdk5), c-Jun N-

terminal kinase (JNK) and ERK1/2 (Robertson et al. 1993; Hanger et al. 1992; Flaherty et al. 2000; Cho and Johnson 2004; Stoothoff and Johnson 2005). Abnormal high phosphorylation is called "hyperphosphorylation". Hyperphosphorylated tau proteins form so called paired helical filaments, which are characteristic for AD. The degradation of tau is inhibited by phosphorylation at the caspase cleavage sites. It has been shown that the mutation of Ser422, which causes a stable phosphorylation at this site, prevents caspase cleavage (Guillozet-Bongaarts et al. 2006). GSK-3β is one of the major tau kinases and is inactivated upon phosphorylation of Akt at Ser9 connecting insulin and IGF-1 signalling to tau phosphorylation. The major tau phosphatase in human brain is PP2A (Sontag et al. 1996), which is as well regulated via the IR/IGF-1R pathway suggesting that IR/IGF-1R signalling maintains an equilibrium of phosphorylation and dephosphorylation of tau (Liu et al. 2008; Millward, Zolnierowicz, and Hemmings 1999).
