Journal ArticleDOI
The structural biology of the amyloid precursor protein APP - a complex puzzle reveals its multi-domain architecture.
TLDR
Current understanding of the structure-function-relationship of the multi-domain protein APP, which consists of the two folded E1 and E2 segments that are connected to one another and to the single transmembrane helix by flexible segments, is summarized.Abstract:
The amyloid precursor protein (APP) and its processing are widely believed to be central for the etiology of Alzheimer's disease (AD) and appear essential for neuronal development and cell homeostasis in mammals. Many studies show the proteolysis of APP by the proteases α-, β- and γ-secretase, functional aspects of the protein and the structure of individual domains. It is, however, largely unclear and currently also widely debated of how the structures of individual domains and their interactions determine the observed functionalities of APP and how they are arranged within the three-dimensional architecture of the entire protein. Further unanswered questions relate to the physiologic function of APP, the regulation of its proteolytic processing and the structural and functional effect of its cellular trafficking and processing. In this review, we summarize our current understanding of the structure-function-relationship of the multi-domain protein APP. This type-I transmembrane protein consists of the two folded E1 and E2 segments that are connected to one another and to the single transmembrane helix by flexible segments and likely fulfills several independent functions.read more
Citations
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Journal ArticleDOI
APP Receptor? To Be or Not To Be
TL;DR: This work focuses on the structural and functional characteristics of APP as a cell surface receptor, and on its interaction with adaptors and signaling proteins.
Journal ArticleDOI
Human Cerebrospinal Fluid Fatty Acid Levels Differ between Supernatant Fluid and Brain-Derived Nanoparticle Fractions, and Are Altered in Alzheimer's Disease
TL;DR: Depleted DHA in CSF fractions in AD is consistent with the importance of n-3 PUFAs in cognitive function, and suggests that disturbed PUFA metabolism contributes to AD pathology, and provides further insight into cell membrane dysfunctions.
Journal ArticleDOI
The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system.
Lucas J. Sosa,Alfredo Cáceres,Sebastian Dupraz,Mariana Oksdath,Santiago Quiroga,Alfredo Lorenzo +5 more
TL;DR: The current knowledge of the physiological role of APP as a cell adhesion molecule and its involvement in key events of neuronal development, such as migration, neurite outgrowth, growth cone pathfinding, and synaptogenesis are focused on.
Journal ArticleDOI
Modeling the complex pathology of Alzheimer's disease in Drosophila.
TL;DR: Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42.
Journal ArticleDOI
The Role of APP in Structural Spine Plasticity
TL;DR: This review article focuses on the mechanisms of APP in structural spine plasticity, which encompasses the morphological alterations at excitatory synapses that occur as changes in the number and morphology of dendritic spines.
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A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60
Xinwei Cao,Thomas C. Südhof +1 more
TL;DR: It is demonstrated that the cytoplasmic tail of APP forms a multimeric complex with the nuclear adaptor protein Fe65 and the histone acetyltransferase Tip60 that stimulates transcription via heterologous Gal4- or LexA-DNA binding domains, suggesting that release of the cytopsized tail ofAPP by γ-cleavage may function in gene expression.
Journal ArticleDOI
Amyloid Precursor Protein Trafficking, Processing, and Function
Gopal Thinakaran,Edward H. Koo +1 more
TL;DR: Molecular characterization of the secretases involved in Aβ production has facilitated cell biological investigations on APP processing and advanced efforts to model AD pathogenesis in animal models.
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