J. Neurochem. (2008) 104, 1433–1439. Glycogen synthase kinase 3 (GSK3) is a constitutively active, proline‐directed serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. GSK3 also plays a pivotal and central role in the pathogenesis of both sporadic and familial forms of Alzheimer’s disease (AD), an observation that has led us to coin the ‘GSK3 hypothesis of AD’. According to this hypothesis, over‐activity of GSK3 accounts for memory impairment, tau hyper‐phosphorylation, increased β‐amyloid production and local plaque‐associated microglial‐mediated inflammatory responses; all of which are hallmark characteristics of AD. If our ‘GSK3 hypothesis of AD’ is substantiated and GSK3 is indeed a causal mediator of AD then inhibitors of GSK3 would provide a novel avenue for therapeutic intervention in this devastating disorder.

Peripheral compartments including blood and cerebrospinal fluid exhibit signals reflecting neuropathological changes in Alzheimer disease (AD).^1,2 In cerebrospinal fluid, these include a decrease in amyloid-β peptide (Aβ) and an increase in total and phosphorylated tau concentrations,³ reflecting amyloid sequestration as plaques and neurofibrillary degeneration, respectively.^4,5 Similarly, while numerous articles suggest that plasma concentrations of several metabolites and proteins might represent responses to neuropathological changes in AD,^6-11 these findings have not been conclusively replicated.¹² A limitation of such studies may be their reliance upon demonstrating changes between affected and unaffected people, a design of study that might identify secondary changes lacking relevance to core disease biology.

Although the mechanism of Aβ action in the pathogenesis of Alzheimer’s disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt–planar cell polarity (PCP)–c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt–PCP–JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt–PCP–JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.

Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying 1001 proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate‐specific antigen complexed to α1‐antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation.

Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD. Alzheimer's disease (AD) is the leading cause of dementia in the ageing population. Symptoms include memory loss and decline in understanding and reasoning. Alois Alzheimer, who reported the first case of AD, observed plaques and tangles in the brains of patients. The plaques are made up of amyloid protein, while the tangles are of tau protein. One of the main scientific ideas about AD is that it starts with build-up of amyloid, which then alters tau protein, causing the disease. Another protein, called GSK-3, also seems to play a part. Simple invertebrates such as flies are useful for understanding human diseases. We have created an AD model in the fruit fly Drosophila where amyloid protein is present in the nerve cells of the adult fly; this caused the flies to be impaired in their survival, nerve function, and behavior. We found that amyloid increased the activity of GSK-3, and so we experimentally turned down its activity and found that this improved the survival and behavior of the flies. Importantly, turning down the activity of GSK-3 in flies that did not have amyloid did not seem to harm them. GSK-3 could therefore be a good target for drugs against AD.