br Materials and Methods br

Materials and Methods
Author Contributions
Conflicts of Interest
Acknowledgments We thank Francine Jodelka for technical assistance and Gopal Thinakaran for the CTM-1 antibody. This work was financially supported by RFUMS internal research funding and NIHS10 OD 010662.
Introduction As the population ages, the physical and mental health of the elderly has drawn increased attention. Dementia, a chronic and neurodegenerative disorder, is one of the top major killers among the old people. Dementia affects nearly 47 million people in the world until April 2017 [1]. Currently, there is no effective treatment to control the progressive process of dementia or cure it. Among various types of dementia, Alzheimer's disease (AD) is the most common one, which is characterized by the progressive loss of neuronal cells and associated with fibrillar 5-lipoxygenase [2,3]. Two prime suspects of AD are neurofibrillary tangles and neuritic plaques. Neurofibrillary tangles are insoluble abnormal fibers inside the brain nerve cells, composed of the microtubule-associated protein tau. Neuritic plaques (also called amyloid plaques), which locate in the spaces between neurons, are deposits due to the aggregation of amyloid β peptide (Aβ) [4]. Several hypotheses have been proposed to explain the pathological causes of AD, including genetics, cholinergic hypothesis, tau hypothesis and amyloid hypothesis. But no hypothesis has been generally accepted. Even so, accumulating evidences show that the familial AD can be caused by the overexpression and mutations of the amyloid precursor protein (APP). Since APP secretes Aβ, the principal component of amyloid plaques [[4], [5], [6], [7], [8], [9]], Aβ is regarded as a key player of AD. The mechanisms of the aggregation and toxicity of Aβ are believed to shed light on the pathology of AD and the cure. Amyloid fibrils are the major forms of Aβ aggregates in amyloid plaques. Amyloid fibrils aggregate via a nucleation-dependent pathway. During the aggregation progress, nucleation and elongation are two dominated stages, which can be described by a lag phase and an elongation phase, respectively. At the lag phase, the nucleus accumulates while Aβ molecules remain mainly as unstructured monomers. At the sequential elongation phase, the Aβ monomers assemble into oligomers, protofibrils and mature fibrils with distinct morphologies [10]. The pathway from monomers to oligomers and then to fibrils is not unidirectional. At the beginning of fibrillation process, monomeric peptide follows the primary nucleation pathway. After the critical concentration of amyloid fibrils formation, the toxic oligomers are produced by the monomeric peptide in a secondary nucleation reaction [11,12]. Overall, Aβ is a leading actor in amyloid fibrils. However, latest studies suggest that only the Aβ is not sufficient to cause fibrillation and neurodegeneration in the brain. In addition, a growing number of findings have demonstrated that, in Aβ aggregates, the intermediates rather than mature amyloid fibrils, might be directly responsible for the toxic effects and the inhibition of critical neuronal activities [[13], [14], [15]]. In the amyloid hypothesis, Aβ aggregation is supposed to be closely related to the interactions between Aβ and cell membranes in the brain. This supposition is reasonable since Aβ is derived from the trans-membrane protein APP through membrane-anchored secretase enzymes and can certainly be proximate to the membrane in space. The supposition is supported by current observations that the cell membranes provide the template for the Aβ fibrillation. Thus, the interactions between Aβ and cell membranes must play a pivotal role in the formation of amyloidal aggregates [[16], [17], [18], [19], [20], [21]]. To illuminate the interactions should have great significance for both the scientific community and clinical applications in AD.