Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Mol Med Rep. 2012 Apr;5(4):1111-5. doi: 10.3892/mmr.2012.774. Epub 2012 Feb 1.
There are several familial forms of Alzheimer's disease (AD) most of which are caused by mutations in the genes that encode the presenilin enzymes involved in the production of amyloid-β (Aβ) from the amyloid precursor protein (APP). In AD, Aβ forms fibrils that are deposited in the brain as plaques. Much of the fibrillar Aβ found in the plaques consists of the 42 amino acid form of Aβ (Aβ1-42) and it is now widely accepted that Aβ is related to the pathogenesis of AD and that Aβ may both impair memory and be neurotoxic. In human cerebrospinal fluid (CSF) several C- and N-terminally truncated Aβ isoforms have been detected and their relative abundance pattern is thought to reflect the production and clearance of Aβ. By using immunoprecipitation and mass spectrometry, we have previously demonstrated that carriers of the familial AD (FAD)-associated PSEN1 A431E mutation have low CSF levels of C-terminally truncated Aβ isoforms shorter than Aβ1-40. Here we replicate this finding in symptomatic carriers of the FAD-causing PSEN1 L286P mutation. Furthermore, we show that preclinical carriers of the PSEN1 M139T mutation may overexpress Aβ1-42 suggesting that this particular mutation may cause AD by stimulating γ-secretase-mediated cleavage at amino acid 42 in the Aβ sequence.
有几种家族性阿尔茨海默病（AD）形式，其中大多数是由编码参与淀粉样前体蛋白（APP）生成淀粉样β（Aβ）的早老素酶的基因突变引起的。在 AD 中，Aβ形成纤维，在大脑中沉积为斑块。在斑块中发现的大部分纤维状 Aβ由 Aβ的 42 个氨基酸形式（Aβ1-42）组成，现在广泛认为 Aβ与 AD 的发病机制有关，Aβ可能既损害记忆又具有神经毒性。在人脑脊液（CSF）中，已经检测到几种 C-和 N-端截断的 Aβ同工型，它们的相对丰度模式被认为反映了 Aβ的产生和清除。通过使用免疫沉淀和质谱法，我们之前已经证明，携带家族性 AD（FAD）相关 PSEN1 A431E 突变的患者脑脊液中 C 端截断的 Aβ同工型水平低于 Aβ1-40。在这里，我们在引起 FAD 的 PSEN1 L286P 突变的有症状携带者中复制了这一发现。此外，我们表明 PSEN1 M139T 突变的临床前携带者可能过度表达 Aβ1-42，这表明该特定突变可能通过刺激 Aβ序列中氨基酸 42 的 γ-分泌酶介导切割而导致 AD。
