Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo microdialysis, cortical and hippocampal dopamine, norepinephrine, and glutamate release during the acquisition of object recognition memory (ORM) in 5-and 10-mo-old triple-transgenic Alzheimer's disease mice (3xTg-AD) and to relate the extracellular changes to 24-h memory performance. Five-and 10-mo-old wild-type mice and 5-mo-old 3xTg-AD showed significant cortical but not hippocampal dopamine increase during object exploration. On a 24-h ORM test, these three groups displayed significant ORM. In contrast, 10-mo-old 3xTg-AD mice showed impaired dopamine release in the insular cortex during ORM acquisition, as well as significant impairment in ORM. In addition, cortical administration of a dopamine reuptake blocker produced an increase of dopamine levels in the 10-mo-old 3xTg-AD mice and attenuated the memory impairment. These data suggest that activation of the dopaminergic system in the insular cortex is involved in object recognition memory, and that dysfunction of this system contributes to the age-related decline in cognitive functioning of the 3xTg-AD mice.Alzheimer's disease (AD) is an age-related and progressive degenerative disorder generally characterized by two neuropathological features: deposits of amyloid-beta (Ab) peptides and neurofibrillary tangles, formed by the hyperphosphorylated microtubulebinding protein tau (Selkoe 2001). These neuropathological features are generally prominent in learning and memory-related brain regions, including the hippocampus, amygdala, and neocortex (Braak and Braak 1991;Nicholson et al. 2010). Because these pathologies are related to synaptic dysfunction leading to neurotransmitter deregulation including acetylcholine deficiency (Davis et al. 1999), several pharmacological therapies for AD focus on the restoration or modulation of cholinergic neurotransmission by acetylcholinesterase inhibitors and muscarinic agonists (Caccamo et al. 2009;Galluzzi et al. 2010). However, there is also evidence that these treatments may increase extracellular levels of dopamine (DA) (Shearman et al. 2006;Preda et al. 2008), suggesting that DA increase may contribute to the therapeutic effect. The possibility that the dopaminergic system may be involved in AD is suggested by evidence of decreased DA levels assessed in post-mortem brain tissue of AD patients (Winblad et al. 1985;Nazarali and Reynolds 1992;Storga et al. 1996), as well as changes in DA receptor distribution and density in several brain structures of the temporal lobe (Joyce et al. 1993(Joyce et al. , 1998Kemppainen et al. 2003;Kumar and Patel 2007).Transgenic models of AD are widely used to study the role of Ab accumulation and tau tangles in the cognitive alterations characteristi...

It is important to understand the biogenesis of exosomes, extracellular vesicles of endosomal origin controlling cell-to-cell communication. We previously reported that Phospholipase D2 (PLD2) supports late endosome (LE) budding and the biogenesis of syntenin-dependent exosomes. Here, we reveal that PLD2 has a broader generic effect on exosome production. Combining gain- and loss-of-function experiments, proteomics, microscopy and lipid-binding studies with reconstituted liposomes mimicking LE, we show that: (i) PLD2 activity controls the recruitment of MVB12B to LE and the exosomal secretion of ESCRT-I; (ii) loss-of-MVB12B phenocopies loss-of-PLD2, similarly affecting LE budding, the number of exosomes released and exosome loading with cargo; (iii) MVB12B MABP domain directly interacts with phosphatidic acid, the product of PLD2. We therefore propose that PLD2 and phosphatidic acid support ESCRT-I recruitment to LE for the formation of exosomes. This work highlights a major unsuspected piece of the molecular framework supporting LE and exosome biogenesis.

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