It is well established that the proteolytic processing of the -amyloid precursor protein (APP) generates -amyloid (A), which plays a central role in the pathogenesis of Alzheimer's disease (AD). In contrast, the physiological role of APP and of its numerous proteolytic fragments and the question of whether a loss of these functions contributes to AD are still unknown. To address this question, we replaced the endogenous APP locus by gene-targeted alleles and generated two lines of knock-in mice that exclusively express APP deletion variants corresponding either to the secreted APP ectodomain (APPs␣) or to a C-terminal (CT) truncation lacking the YENPTY interaction motif (APP⌬CT15). Interestingly, the ⌬CT15 deletion resulted in reduced turnover of holoAPP, increased cell surface expression, and strongly reduced A levels in brain, likely because of reduced processing in the endocytic pathway. Most importantly, we demonstrate that in both APP knock-in lines the expression of APP N-terminal domains either grossly attenuated or completely rescued the prominent deficits of APP knock-out mice, such as reductions in brain and body weight, grip strength deficits, alterations in circadian locomotor activity, exploratory activity, and the impairment in spatial learning and long-term potentiation. Together, our data suggest that the APP C terminus is dispensable and that APPs␣ is sufficient to mediate the physiological functions of APP assessed by these tests.
Our results demonstrate that these connexins play a dual crucial role in inner ear Ca 2؉ signaling: as hemichannels, they promote ATP release, sustaining long-range ICS propagation; as GJ channels, they allow diffusion of Ca 2؉ -mobilizing second messengers across coupled cells.deafness ͉ mouse models ͉ P2x7 receptor ͉ pannexin ͉ biosensor cells
Gap junctions consist of intercellular channels dedicated to providing a direct pathway for ionic and biochemical communication between contacting cells. After an initial burst of publications describing electrical coupling in the brain, gap junctions progressively became less fashionable among neurobiologists, as the consensus was that this form of synaptic transmission would play a minimal role in shaping neuronal activity in higher vertebrates. Several new findings over the last decade (e.g. the implication of connexins in genetic diseases of the nervous system, in processing sensory information and in synchronizing the activity of neuronal networks) have brought gap junctions back into the spotlight. The appearance of gap junctional coupling in the nervous system is developmentally regulated, restricted to distinct cell types and persists after the establishment of chemical synapses, thus suggesting that this form of cell-cell signaling may be functionally interrelated with, rather than alternative to chemical transmission. This review focuses on gap junctions between neurons and summarizes the available data, derived from molecular, biological, electrophysiological, and genetic approaches, that are contributing to a new appreciation of their role in brain function.
γ‐Secretase‐dependent regulated intramembrane proteolysis of amyloid precursor protein (APP) releases the APP intracellular domain (AICD). The question of whether this domain, like the Notch intracellular domain, is involved in nuclear signalling is highly controversial. Although some reports suggest that AICD regulates the expression of KAI1, glycogen synthase kinase‐3β, Neprilysin and APP, we found no consistent effects of γ‐secretase inhibitors or of genetic deficiencies in the γ‐secretase complex or the APP family on the expression levels of these genes in cells and tissues. Finally, we demonstrate that Fe65, an important AICD‐binding protein, transactivates a wide variety of different promoters, including the viral simian virus 40 promoter, independent of AICD coexpression. Overall, the four currently proposed target genes are at best indirectly and weakly influenced by APP processing. Therefore, inhibition of APP processing to decrease Aβ generation in Alzheimer's disease will not interfere significantly with the function of these genes.
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