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Synapses are fundamental signaling units of the central nervous system that mediate communication between individual neurons, participate in the computation of neuronal networks, and process information through long-term modification of their strength and structure. The normal function of the central nervous system critically depends on the establishment of ‘precise’ synaptic connections between neurons and specific target cells. During synaptogenesis, synapses form, mature, stabilize, and are eliminated through processes that require intimate communication between pre- and postsynaptic partners. The sequential and/or parallel processes dictate the wiring of neural circuits in a rapid and dynamic fashion. Accumulating evidence suggests that activity-dependent synaptic and circuit plasticity reflects the assembly and disassembly of diverse synapses that occur in a distinctive manner in specific neuron types. In this Research Topic, our purpose is to compile the latest developments in our understanding of molecular and cellular mechanisms underlying pre- and postsynaptic assembly, specification of synaptic adhesion pathways, presynaptic neurotransmitter release and postsynaptic receptor trafficking. In addition, non-neuronal cell processes involved in dismantling and eliminating synapses and relevant neural circuits will be covered. Clinical implications of this research topic will be considered, emphasizing the importance of these basic neuroscience research activities for translational and therapeutic applications. This includes literature describing recent methodologies for probing key issues regarding assembly/disassembly of synapses and circuits as well as primary research articles that provide critical insights into these fundamental questions in various model systems and experimental preparations.

Synaptic adhesion molecule --- Neuron --- neural circuit assembly --- recognition --- synapse

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The amyloid precursor protein APP plays a key role in the pathogenesis of Alzheimer’s disease (AD), as proteolytical cleavage of APP gives rise to the Aß peptide which is deposited in the brains of Alzheimer patients. Despite this, our knowledge of the normal cell biological and physiological functions of APP and the closely related APLPs is limited. This may have hampered our understanding of AD, since evidence has accumulated that not only the production of the Aß peptide but also the loss of APP-mediated functions may contribute to AD pathogenesis. Thus, it appears timely and highly relevant to elucidate the functions of the APP gene family from the molecular level to their role in the intact organism, i.e. in the context of nervous system development, synapse formation and adult synapse function, as well as neural homeostasis and aging. Why is our understanding of the APP functions so limited? APP and the APLPs are multifunctional proteins that undergo complex proteolytical processing. They give rise to an almost bewildering array of different fragments that may each subserve specific functions. While Aß is aggregation prone and neurotoxic, the large secreted ectodomain APPsa - produced in the non-amyloidogenic a-secretase pathway - has been shown to be neurotrophic, neuroprotective and relevant for synaptic plasticity, learning and memory. Recently, novel APP cleavage pathways and enzymes have been discovered that have gained much attention not only with respect to AD but also regarding their role in normal brain physiology. In addition to the various cleavage products, there is also solid evidence that APP family proteins mediate important functions as transmembrane cell surface molecules, most notably in synaptic adhesion and cell surface signaling. Elucidating in more detail the molecular mechanisms underlying these divers functions thus calls for an interdisciplinary approach ranging from the structural level to the analysis in model organisms. Thus, in this research topic of Frontiers we compile reviews and original studies, covering our current knowledge of the physiological functions of this intriguing and medically important protein family.

Amyloid precursor-like protein --- learning and memory --- neuroprotection --- spines --- synaptic plasticity --- Alzheimers disease --- animal model --- synaptogenesis --- synaptic adhesion --- Amyloid precursor protein

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The amyloid precursor protein APP plays a key role in the pathogenesis of Alzheimer’s disease (AD), as proteolytical cleavage of APP gives rise to the Aß peptide which is deposited in the brains of Alzheimer patients. Despite this, our knowledge of the normal cell biological and physiological functions of APP and the closely related APLPs is limited. This may have hampered our understanding of AD, since evidence has accumulated that not only the production of the Aß peptide but also the loss of APP-mediated functions may contribute to AD pathogenesis. Thus, it appears timely and highly relevant to elucidate the functions of the APP gene family from the molecular level to their role in the intact organism, i.e. in the context of nervous system development, synapse formation and adult synapse function, as well as neural homeostasis and aging. Why is our understanding of the APP functions so limited? APP and the APLPs are multifunctional proteins that undergo complex proteolytical processing. They give rise to an almost bewildering array of different fragments that may each subserve specific functions. While Aß is aggregation prone and neurotoxic, the large secreted ectodomain APPsa - produced in the non-amyloidogenic a-secretase pathway - has been shown to be neurotrophic, neuroprotective and relevant for synaptic plasticity, learning and memory. Recently, novel APP cleavage pathways and enzymes have been discovered that have gained much attention not only with respect to AD but also regarding their role in normal brain physiology. In addition to the various cleavage products, there is also solid evidence that APP family proteins mediate important functions as transmembrane cell surface molecules, most notably in synaptic adhesion and cell surface signaling. Elucidating in more detail the molecular mechanisms underlying these divers functions thus calls for an interdisciplinary approach ranging from the structural level to the analysis in model organisms. Thus, in this research topic of Frontiers we compile reviews and original studies, covering our current knowledge of the physiological functions of this intriguing and medically important protein family.

Amyloid precursor-like protein --- learning and memory --- neuroprotection --- spines --- synaptic plasticity --- Alzheimers disease --- animal model --- synaptogenesis --- synaptic adhesion --- Amyloid precursor protein