Cytoskeleton disturbance in Alzheimer’s disease: a molecular and cellular study – MAALAD

The neuropathology of Alzheimer’s disease (AD) is characterized by both the accumulation of extracellular plaques containing Aß peptides, derived from ß-amyloid protein, and the formation of intra-neuronal fibrillary tangles composed of tau, a neuronal microtubule-associated protein. A key to understand the actions of Aß and tau in Alzheimer disease (AD) is to determine how these proteins affect the neuronal networks in which memories are stored, thereby causing dementia. Recent studies have revealed that loss of synapses is substantially greater than could be explained by the loss of neurons, which indicates that a deficit of synapses might be a primary problem in the early phases of AD. Synapses constitute communication sites between neurons and are composed of presynaptic (axon terminal) and post-synaptic (dendritic spines) compartments. Dendritic spines, which represent the receptive region of most excitatory synapses, are structurally heterogeneous, varying in volume and number. It has been clearly established that their morphology characterizes synaptic functionality, suggesting that spine morphological studies are crucial for understanding higher brain functions such as learning and memory. A defining characteristic of spines is that they are rich in actin. The search for the molecular understanding of spine structure and functions has also highlighted the role of microtubules in these processes. Actin cytoskeleton and microtubules are known to be central to morphologic changes of neurons during development and more recent data suggest the direct implication of these two cytoskeletal polymers in synaptic plasticity events in adults, although the precise underlying mechanisms are still unclear. Preliminary data obtained by partner 1 indicate that Aß can induce actin disorganisation in dendritic spines. Also, direct interactions between Aß, Tau and cytoskeletal elements have been reported; in particular, Aß requires Tau to induce microtubule alteration in cells and, at least in drosophila, Aß peptides synergistically enhance the ability of tau to promote alterations in the actin cytoskeleton, which subsequently trigger neurodegeneration. Furthermore, several lines of evidence suggest that non-fibrillar Aß, instead of fibrillar one, and soluble tau (wild-type and/or mutated forms) might be the “toxic” species directly responsible for these impairments.
The aim of the “MAALAD” proposal is to characterize Microtubule and Actin Alterations in early phases of AD at molecular and cellular levels. For this purpose, we gather 3 research groups studying cytoskeleton organization and dynamics as well as neuronal morphology and functions with complementary in vitro and in vivo approaches. We will analyse actin and microtubule changes induced by two major players of AD, Aß oligomers and tau proteins (wild-type and mutated versions), and assess consequences of these perturbations on spine morphology and functions. For that, cytoskeleton properties will be studied in classical cellular models, as well as in neuronal cultures where they will be correlated to more physiological aspects, such as spine morphology and activity. In parallel, we intend to describe the molecular basis of Aß/tau-induced alterations of the cytoskeleton by using cell-free systems reconstituted from purified components. Altogether, results should allow dissecting molecular pathways leading to cytoskeleton changes and spine dysfunctions in AD, and give a better understanding of early memory deficit causes in this disease.