کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8684630 | 1580133 | 2018 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
sAPPβ and sAPPα increase structural complexity and E/I input ratio in primary hippocampal neurons and alter Ca2+ homeostasis and CREB1-signaling
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کلمات کلیدی
CREBeGFPAMPA-RBACEAβHRPAPPBDNF - BDNF یا فاکتور نورونزایی مشتقشده از مغز α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor - α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptorADAM - آدامamyloid β - آمیلوئید βhorse-radish peroxidase - اسب پریکسیداز تربچهγ-aminobutyric acid - اسید γ-آمینوبوتیریکLoad - بارAlzheimer's disease - بیماری آلزایمرLate-onset Alzheimer's disease - بیماری آلزایمر در شروع زودرسCNS - دستگاه عصبی مرکزیDIV - دیوdays in vitro - روز in vitroLSM - سازمان غیر دولتیcentral nervous system - سیستم عصبی مرکزیBrain-derived neurotrophic factor - فاکتور نوروتروفی مشتق شده از مغزCSF - مایع مغزی نخاعیCerebrospinal fluid - مایع مغزی نخاعیcAMP-response element binding protein - پروتئین اتصال دهنده عنصر cAMPenhanced green fluorescent protein - پروتئین فلورسنت سبز افزایش یافته استamyloid precursor protein - پروتئین پیش ماده آمیلوئیGABA - گابا
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
عصب شناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid β (Aβ). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aβ production and soluble APPβ (sAPPβ) levels. Aβ is known to impair synaptic function; however, much less is known about the physiological functions of sAPPβ. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPβ exist. The intracellular pathways of sAPPβ are largely unknown. Since sAPPβ is generated alongside Aβ by β-secretase (BACE1) cleavage, we tested the hypothesis that sAPPβ effects differ from sAPPα effects as a neurotrophic factor. We therefore performed a head-to-head comparison of both mammalian recombinant peptides in developing primary hippocampal neurons (PHN). We found that sAPPα significantly increases axon length (pâ¯=â¯0.0002) and that both sAPPα and sAPPβ increase neurite number (pâ¯<â¯0.0001) of PHN at 7â¯days in culture (DIV7) but not at DIV4. Moreover, both sAPPα- and sAPPβ-treated neurons showed a higher neuritic complexity in Sholl analysis. The number of glutamatergic synapses (pâ¯<â¯0.0001), as well as layer thickness of postsynaptic densities (PSDs), were significantly increased, and GABAergic synapses decreased upon sAPP overexpression in PHN. Furthermore, we showed that sAPPα enhances ERK and CREB1 phosphorylation upon glutamate stimulation at DIV7, but not DIV4 or DIV14. These neurotrophic effects are further associated with increased glutamate sensitivity and CREB1-signaling. Finally, we found that sAPPα levels are significantly reduced in brain homogenates of AD patients compared to control subjects. Taken together, our data indicate critical stage-dependent roles of sAPPs in the developing glutamatergic system in vitro, which might help to understand deleterious consequences of altered APP shedding in AD patients, beyond Aβ pathophysiology.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Experimental Neurology - Volume 304, June 2018, Pages 1-13
Journal: Experimental Neurology - Volume 304, June 2018, Pages 1-13
نویسندگان
Raphael Hesse, Bjoern von Einem, Franziska Wagner, Patricia Bott, Daniel Schwanzar, Rosemary J. Jackson, Karl Josef Föhr, Ludwig Lausser, Katja S. Kroker, Christian Proepper, Paul Walther, Hans A. Kestler, Tara L. Spires-Jones, Tobias Boeckers,