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” This timely short review by Medway and Morgan discusses the recent advances in understanding the genetics of late onset, or sporadic, Alzheimer’s disease (sAD). The power of meta-analysis of genome-wide association studies has identified
eleven new genes implicated in sAD and, together with previous information, the susceptibility loci identified now account for around 61% of the population attributable risk. The newly identified genes highlight pathways of potential importance for disease pathogenesis and for the exploration of possible therapeutic targets. The possible roles of these genes, which are involved in diverse pathways including
amyloid precursor trafficking, MAP-kinase signalling, synaptic plasticity and cell adhesion, are discussed. It is of particular interest that genetic studies give insight into LDE225 a role for the immune system and microglia in neurodegeneration and may point to shared mechanisms with bone disease. Genetic models and the future of genetic studies in sAD are considered. In addition to tangle and plaque formation, loss of basal forebrain cholinergic neurons is an important component of the pathology of Alzheimer’s disease. Loss of these projection neurons leads to cortical cholinergic deficit that is a target of current Alzheimer’s drug therapies. However, whilst existing transgenic models can reproduce β-amyloid and tau pathology, they do not recapitulate the cholinergic degeneration. Hartig et al. have now used an elegant immunolesioning technique to induce loss of basal forebrain cholinergic neurons in a triple transgenic model with
β-amyloid and tau pathology. They show effective cholinergic neuron depletion and demonstrate that this results in elevated amyloid precursor protein, Aβ and phosphorylated tau, and in increased gliosis around plaques. This approach, combining ‘molecular surgery’ with transgenic technology offers a method to model Bay 11-7085 the complexity of Alzheimer’s disease and explore the interactions of its cellular and molecular pathologies. Neurofibrillary tangle formation is a key pathological event in Alzheimer’s disease and other tauopathies. It is also seen in the brains of individuals with Down syndrome by their forties. Tau protein is a key component of tangles, where it shows a variety of modifications including phosphorylation at multiple sites, conformational change and cleavage. Mondragon-Rodrigues et al. have now further defined the sequence of tau modification. They show that phosphorylation at the carboxy-terminus of the molecule is an early event, occurring at prefibrillar stages, and that a similar sequence of changes is seen in both Alzheimer’s and Down syndrome.