SummarySynaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's Disease; yet, the molecular mechanisms underlying synaptic failure are unknown. Here we report a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines, and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's Disease. We show that, in spines, caspase-3 activates calcineurin which, in turn, triggers dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from post-synaptic sites. These molecular modifications lead to alterations of glutamatergic synaptic transmission and plasticity, and correlate with spine degeneration and a deficit in hippocampal-dependent memory. Importantly, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescues the observed Alzheimerlike phenotypes. Therefore, we identify a novel caspase-3-dependent mechanism driving synaptic failure and contributing to cognitive dysfunction in Alzheimer's Disease. These findings point to caspase-3 as possible avenues for pharmacological therapy during early disease stages.Episodic hippocampal-dependent memory loss, the earliest clinical sign of Alzheimer's disease, is thought to be due to changes in synaptic function rather than neuronal loss 1,2 . Specifically, functional brain imaging studies revealed hippocampal mild abnormalities prior to clinical diagnosis and in the absence of structural brain atrophy, suggesting an altered functional connectivity of hippocampus at early stages of disease [3][4][5] .Dendritic spines are likely to be the first affected synaptic elements during early cognitive decline 6 . This is supported by several lines of evidence, such as: i) hippocampal spine-mediated plasticity underlies learning and memory 7 ; ii) post-mortem hippocampus from Alzheimer patients shows a significant decrease in dendritic spine density compared to age-matched controls 8 and iii) transgenic 3 mice expressing mutated forms of the amyloid precursor protein (APP), associated with familial Alzheimer's Disease, show age-dependent reductions in spine density, prior to plaque deposition 9 .Nevertheless, the molecular link between APP mutations triggering Alzheimer's Disease, and the occurrence of early spine loss remains elusive. Interestingly, a localized caspase-3 activity, causing synaptic failure, has been observed in vitro 10 , but the molecular mechanism linking caspase-3 activity to synaptic loss is far from being elucidated.Here, we analyzed caspase-3 activity in hippocampal synapses of the Tg2576 transgenic mouse model, harboring the human APPswe mutant allele linked to familial Alzheimer's Disease 11 . These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is r...

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Current research on the origin of life typically focuses on the self-organisation of molecular components in individual cell-like compartments, thereby bringing about the emergence of self-sustaining minimal cells. This is justified by the fact that single cells are the minimal forms of life. No attempts have been made to investigate the cooperative mechanisms that could derive from the assembly of individual compartments. Here we present a novel experimental approach based on vesicles "colonies" as a model of primitive cell communities. Experiments show that several advantages could have favoured primitive cell colonies when compared with isolated primitive cells. In fact there are two novel unexpected features typical of vesicle colonies, namely solute capture and vesicle fusion, which can be seen as the basic physicochemical mechanisms at the origin of life.

Background: Before constriction ZipA anchors FtsZ to the E. coli inner membrane as part of the cell division proto-ring. Results: Dynamic FtsZ polymers shrink ZipA-containing vesicles whereas excess of ZipA invaginates the E. coli membrane destroying the permeability barrier. Conclusion: Constriction forces can be evidenced both in bacteria and in vesicles. Significance: Defined bacterial elements reproduce division functions when assembled in vitro.