This study examines (1) whether L2 learners’ oral fluency and accuracy improve through conversation practice with AI tutors in a Japanese language learning app, (2) when fluency increases, and (3) which learning cycle is most effective. Ten participants joined the study and practiced conversations with Kaizen Languages’ AI tutors for three weeks. Learners selected their preferred learning cycle: a group with fewer lessons to complete per day but more practice days per week or a group with more lessons to complete per day but less frequent practice days per week. After three weeks of self-study, participants took an oral test to show how much they improved their fluency and accuracy in new contexts. The results of this study show that not only did learners’ oral fluency improve with the use of the Kaizen app, but their oral accuracy also increased. In addition, learners who improved their fluency practiced repeatedly, and their fluency improved until three or four repetitive practices. Although this study did not find an effective learning cycle, it implies that the ideal learning cycle requires at least three times of practice to improve fluency, while five to six times of practice produces higher accuracy.

This dissertation seeks to understand travel satisfaction, travel affinity, and other psychological factors in relation to travel demand, such as the desire for trip making, willingness to spend time traveling, and choice of travel mode. The research was based on the Mood State in Transport Environments survey of 247 Android users (about 6,000 completed trip surveys) in the Blacksburg-Roanoke, VA, Washington, DC, and Minneapolis, MN metropolitan areas from fall 2016 to spring 2018. Respondents answered an entry survey, tracked their travel for 7 days, and answered a trip survey associated with each trip. The dataset provides opportunities to examine travel and activities during travel at the within- and between-person levels. Three studies in this dissertation examined three measures of the positive utility of travel and their relationship with travel behavior. I quantified (1) the desirability of trip making, (2) the ideal travel time related to different travel characteristics, and (3) the effect of satisfaction on commute mode choice. The first study examines the patterns of travel affinity with various travel modes, trip purposes, and activities during the trip. Travel affinity was measured by asking the willingness to forgo a trip when there is an opportunity to do so. I found that this is a valid and strong measure of the positive utility of travel. Travelers were more willing to make trips when they traveled on foot or bicycle, talked with someone during the trip, and took shorter trips. Additionally, commute trips were less likely to be enjoyed as compared to other, non-commute trips. The second study focused on (1) testing the validity of the "ideal travel time" measurement and (2) measuring factors associated with the willingness to spend time traveling. I found that although ideal travel time was a strong measure of the positive utility of travel, it was very weakly associated with the desirability of trip making and satisfaction with trips. Although few people wanted zero commute time (3%), the number of trips that had zero ideal travel time was much higher (16%), indicating that the desired travel amount may vary across different trip and environmental characteristics and purpose. Ideal travel time was longer for active travel trips, leisure trips, when conducting activities during trips (e.g., talking, using the phone, looking at the landscape), when traveling with companions and during the weekend. The third study investigated the role of travel satisfaction and attitude in mode choice behavior. This is one of the very few studies that have considered the role of these psychological factors in multimodal mode choice based on revealed preference data. I found that satisfaction and attitude toward modes and travel played a significant role in the choice model; it also modified the role of travel time in the models. However, the perception of travel time usefulness was insignificant in the model. Scenario analyses based on the model results showed that it is optimal to invest in active transportation and public transit at the same time in order to shift car drivers to these sustainable modes. These studies contribute to the small but growing body of literature on the positive utility of travel and transrational decision making in transportation. It is the only study that employed a smartphone survey with a repeated measure of trips over the course of 1-2 weeks. The third study is among the earliest attempts to include satisfaction and attitude together into mode choice models. This dissertation has several implications for research and practice. First, it calls for better measurements of well-being and satisfaction. Second, models with appropriate psychological factors would more realistically resemble actual travel behavior. Including satisfaction in the choice model changes the coefficient of travel time (and potentially cost), which modifies the value of travel time savings, a basis of most benefit-cost analyses in transportation planning and engineering. Better mode choice and trip generation models will generate more reliable predictions of future infrastructure use and investment. Third, studies of travel affinity (positive utility of travel) have implications for demand modeling and management practice. Practitioners should reevaluate the effectiveness of travel demand management strategies aimed at reducing travel time and trips, such as congestion pricing (e.g., tolls), online shopping, and telecommuting. / Doctor of Philosophy / People have various motivations to travel every day. For some, traveling is a means to an end to get from one place to another. Their main travel purpose is to perform some activities at destinations, such as grocery shopping, working, or visiting a friend. For others, traveling is a joy to get some fresh air, to be on one’s own company, to enjoy driving or exercising (while walking or bicycling), in addition to conducting activities at destinations. This idea of traveling for fun is still unpopular in transportation research. This dissertation seeks to understand the patterns of travel and motivations: who are traveling for fun, and when? Whether this affinity and satisfaction for travel drive people’s decision to choose a travel mode? To answer these questions, I measured the affinity for travel in two ways: willingness to make trips (i.e., travel from one place to another) and desired amount of time spent on travel. I found that people were willing to travel more when they conducted certain activities during trips, such as talking to others, talking on the phone, or other activities. Commuting was less fun as compared to other travel purposes, such as socializing or leisure. Bicyclists and pedestrians liked their trips and wanted to travel more than car drivers and bus users. People who were satisfied with their commute trips made by one mode would be more likely to use that mode for commuting. The affinity for travel is relevant to urban residents’ mental well-being and demand for travel, which translate into health and congestion relief benefits. The results from my studies suggest that more attentions on traveling for fun and multitasking should be paid to account for future mobility options, such as ride hailing (e.g., Uber, Lyft) and autonomous vehicles. These modes have promised fun from activities during travel, the autonomy, and convenience, and thus would generate more traffic on the road while providing less social and environmental benefits. The results from this dissertation would inform city planners, engineers, and health practitioners on planning for sustainable cities by improving well-being for transportation users and accommodate sustainable modes of transport, such as bicycling, walking, and transit by providing users with safe and satisfactory travel environments. The results also imply potential pitfalls of the current planning practice such as overestimating the value of travel time savings, benefit-cost analyses, and the effectiveness of travel demand management strategies, such as telecommuting and using information and communications, in reducing travel.

Neuronal models for Alzheimer's disease research frequently have limitations as a result of their nonhuman origin and/or transformed state. Here we examined the potential of readily accessible neural crest-derived human epidermal melanocytes isolated from elderly individuals as a model system for Alzheimer's disease research. The amyloidogenic isoforms of amyloid precursor protein (APP; isoforms APP751/770) and amyloid beta (A¿)1¿40 were detected in epidermal melanocytes using immunocytochemistry and western blotting. Incubation of epidermal melanocytes with aggregated A¿1¿40 peptide caused a concentration-dependent reduction in cell viability, whereas age-matched dermal fibroblasts remained unaffected. These findings suggest that epidermal melanocytes from elderly donors are capable of amyloidogenesis and are sensitive to A¿1¿40 cytotoxicity. Thus, these cells may provide a readily accessible human cell model for Alzheimer's disease research.

Yes / A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling. / Wellcome Trust, Grant/Award Number: 200646/Z/16/Z

Background: Web application security (WAS) testing is crucial for protecting web applications from cyber threats. However, organizations often struggle to select effective WAS testing tools due to the lack of a well-defined set of evaluation criteria. This research aims to address this need by identifying the key metrics for evaluating and comparing WAS testing tools.  Objectives: The primary objectives of this research are to identify the key metrics for comparing WAS testing tools, validate the significance of these metrics through semi-structured interviews, and perform a comparison between WAS testing tools using the validated metrics. This research aims to find a set of validated metrics for evaluating and comparing WAS testing tools.  Methods: The research methodology consisted of three main phases: a literature review to compile a comprehensive set of technical and non-technical metrics commonly used for assessing and comparing WAS testing tools, semi-structured interviews with security experts to validate the significance of the identified metrics, and an experiment to compare three WAS testing tools - ZAP, Burp Suite, and Acunetix - using the OWASP Benchmark project. These three tools were selected based on the author’s recommendations in the literature.  Results: The initial literature review found 37 evaluation metrics for WAS testing tools. Through interviews, experts confirmed some of these were important, but also said some were not very useful. The experts additionally suggested some new metrics that were not in the literature. Incorporating this feedback, the final list was refined down to 35 metrics for evaluating WAS testing tools. An experiment was then conducted to compare three WAS testing tools - ZAP, Burp Suite, and Acunetix with the test subject as the OWASP Benchmark Project and by using the validated set of metrics. The results of this experiment revealed differences in the performance of the tools, with Burp Suite emerging as the best performer.  Conclusions: This research has provided a valid set of metrics for comparing and evaluating WAS testing tools, empowering organizations to make more informed decisions. Security professionals can optimise their WAS testing tool selection by understanding the key metrics and their relative significance, as established through the literature and interviews. Based on the experimental analysis, Burp Suite performed better than other tools. Therefore, for organizations initiating the selection process of the WAS testing tool, Burp Suite stands out as a good choice.

The "SmartCane+" thesis abstract outlines an initiative aimed at improving conventional walking canes into more intelligent, helpful devices for senior citizens. The incorporation of microcontrollers, which permits wireless communication and connection functions, is the primary innovation. With the use of MIT App Inventor, a unique mobile application and this technology, the cane can send its position to the user using Bluetooth. Because it can stop the cane from becoming lost, which is a regular problem for senior users, this function is especially beneficial. The SmartCane+ design places a strong focus on accessibility and cost. The idea maintains cheaper prices and simpler technology by choosing not to add complex hardware, which makes it easier for consumers to embrace and operate without feeling overwhelmed by complexity. By striking a mix between cutting-edge technology and intuitive operation, the design hopes to keep the cane a help rather than a burden. The results of the project indicate that the SmartCane+ effectively improves the safety and independence of senior users by ensuring the cane remains within a reachable distance and providing timely alerts. Testing showed reliable performance in various environments, although closed spaces introduced more variability. Future work will focus on enhancing the system’s accuracy, optimizing power consumption, and expanding compatibility with other mobile platforms.

本研究重點欲探討時下人人皆有的心理狀態「寂寞感」、「交友軟體的使用動機」與「自我揭露」行為之間的關係、而「交友軟體品質特性」又如何調節影響「交友軟體使用動機」與「自我揭露」行為。本研究採取網路問卷調查的方式，對於交友App有使用經驗的使用者為主要調查對象，共計307有效問卷進行分析。本研究主要發現如下： 1.本研究的受試者以男性、年齡18-25歲、學歷以大專院校者為最多，感情狀況以未婚族群最多，但是還是有非單身甚至已婚交友用戶；使用交友軟體的時間大多兩年之內，平均下載2.66個交友App軟體，其中最常使用的交友App軟體為Beetalk。受試者平均每週上交友軟體的天數為5.07天，每週花費5.43小時。另外，高達94.1%的受試者曾經在交友App平台上與陌生人進一步用其他通訊軟體、社群媒體互動，並有88.9%的受試者曾約現實碰面。 2.寂寞感程度可顯著的正向預測交友軟體使用動機中的日常社交、社會逃避以及尋愛之三個構面。 3.寂寞感程度可顯著的正向預測自我揭露中的誠實度、數量以及正負向之三個構面。 4.關於交友軟體使用動機(日常社交、社會逃避、尋愛)與自我揭露(誠實度、數量、正負向)之間的關係：交友軟體使用動機中日常社交、社會逃避與尋愛之三個構面皆可顯著預測自我揭露中的誠實度：當日常社交和社會逃避動機越高時，自我揭露中的誠實度越高；但是當尋愛動機越高時，自我揭露中的誠實度越低。交友使用動機中日常社交和尋愛之二個構面皆可顯著預測自我揭露中的數量：當日常社交動機越高時，自我揭露中的數量越高；但當尋愛動機越高時，自我揭露中的數量越低。交友使用動機中日常社交之構面可顯著正向預測自我揭露中的正負向。 5.交友軟體品質特性(使用者介面、安全性、形象聲譽、會員素質、尋愛達成率)對交友軟體使用動機與自我揭露的調節效果中，僅只有尋愛達成率對交友軟體使用動機和自我揭露產生調節效果。 6.交友軟體使用動機中僅有日常社交之構面對於寂寞感程度與自我揭露有中介效果。 / The purpose of this study is to explore how “loneliness” which is widely prevalent throughout the society affects the motives of using online dating applications and the behavior of self-disclosure. Furthermore, how the quality of online dating apps operates in between the motives of using online dating apps and the behavior of self- disclosure. Online survey was conducted and 307 respondents completed the questionnaire. The research results are presented as follow: 1.Most of the respondents in the study are male, aged from 18 to 25, graduated from college and are currently single. Still, there are some of them in a relationship and even married. Subjects mostly have been used the dating apps less than 2 years, and averagely downloaded 2.66 dating apps. Furthermore, the most popular dating apps is Beetalk. Respondents use dating apps 5.07 days a week and 5.43 hours a week in average. Besides, there are 94.1% of the respondents have used other social media or social apps to communicate with other users they met in dating apps and 88.9% of the respondents have actually met up in real life. 2.Different degree of loneliness have statistically significant and positive predictable effect on the motives of using online dating apps including “Daily Social Needs”, “Escape to Virtual World”, and “Romance”. 3.Different degree of loneliness have statistically significant and positive predictable effect on the different aspects of self-disclosure including: Honesty, Quantity, and Positivity. 4.The motives of using online dating apps including “Daily Social Needs”, “Escape to Virtual World”, “Romance” have statistically significant and predictable effect on the honesty of self-disclosure. “Daily Social Needs” and “Romance” of motives have significant and predicable effect on the quantity of self-disclosure. Only “Daily social needs” have statistically significant and predictable effect on the positivity of self-disclosure. 5.Only the quality of “Love Achievement Rate” of online dating apps have operation effects in between the motives of using online dating apps and the behavior of self- disclosure. 6.Only “Daily social needs” of motives of using online dating apps have mediation effects between loneliness and the behavior of self disclosure.

This Master's degree thesis deals with a specific area of creative industries: development of mobile applications. The aim is to identify and understand the work routines of Czech iOS developers while considering the importance of design as one of the benchmarks of mobile application quality on the Apple App Store. I mainly focus on mapping work routines of selected developers and their thinking about design in the context of Apple devices and iOS platform, assuming that Apple establishes a high standard of visual and functional qualities. I am addressing an issue of application usability not only in terms of design of the user interface, but also its functioning and more aspects of application development within the ecosystem of Czech mobile app industry. The theoretical part of my thesis subjectively describes fundamental concepts from the mobile app development field and theories related to the topic. Empirical part of the study is based on qualitative interviews with 9 Czech mobile app developers and following thematic analysis. This study can serve as an interesting resource of understanding of the work of Czech mobile app developers, how they think about design and Apple as a platform or as a solid foundation for further quantitative investigation to confirm or revise my findings.

Une des principales caractéristiques de la maladie d'Alzheimer (MA) est l'accumulation intracérébrale du peptide neurotoxique Amyloïde β (Aβ) sous forme oligomérique et sous forme agrégée en plaques amyloïdes. Ce peptide est le produit du clivage de l'Amyloid Precursor Protein (APP) selon la voie amyloïdogène, voie pathologique suractivée dans la MA. La majorité des recherches, au cours des 25 dernières années, se sont concentrées sur les conséquences pathologiques de cette dérégulation, mettant au second plan la compréhension des fonctions physiologiques de l’APP. Cependant, de nombreuses études montrent que ses fonctions physiologiques pourraient être médiées par ses formes solubles (APPs). Dans la voie de clivage physiologique, la voie non-amyloïdogène, l’APP est clivé par l’α secrétase pour libérer l’APPsα, peptide disposant de propriétés neuroprotectrices et synaptotrophiques, essentielles au bon fonctionnement cérébral. Dans le contexte de la MA, la suractivation de la voie amyloïdogène va aboutir à la production de l’APPsβ au détriment de celle d’APPsα. Les conséquences fonctionnelles associées à la maladie d’Alzheimer pourraient ainsi être dues à la diminution de la production d’APPsα associée à une augmentation de la production d’APPsβ. Mon projet de thèse porta sur les conséquences mnésiques et fonctionnelles de la surexpression de ces deux formes et à leur potentiel thérapeutique dans la maladie d’Alzheimer. Nous avons tout d’abord surexprimé l’APPsα dans les neurones de l’hippocampe de souris transgéniques APP/PS1ΔE9, modèle de la MA, qui présentent des déficits cognitifs et synaptiques. L’expression continue d’APPsα, à l’aide de vecteurs AAV, permet la restauration des performances mnésiques des souris, de la potentialisation à long terme (LTP) ainsi que du nombre d’épines dendritiques dans l’hippocampe. Ce sauvetage phénotypique s’accompagne de la diminution conjointe des niveaux d’Aβ et des plaques amyloïdes. Ceci serait en partie la conséquence de l’activation de la microglie, type cellulaire ayant la capacité d’internaliser et de dégrader l’Aβ. Mon second axe de recherche a consisté à étudier l’APPsβ dont l’implication dans la MA reste méconnue. Sa surexpression dans le modèle murin APP/PS1ΔE9 n’induit pas de restauration de la LTP ni de la mémoire spatiale. Néanmoins, l’injection d’APPsβ aboutit à la diminution de la concentration en Aβ solubles sans cependant réduire le nombre de plaques amyloïdes. Ce défaut pourrait-être la conséquence de l’absence d’activation microgliale. En résumé, mon travail de thèse montre que, contrairement à l’APPsβ, la surexpression d’APPsα pourrait contrecarrer l’évolution inéluctable de la maladie et en particulier en réduisant l’atteinte synaptique et mnésique caractéristique de la MA. Ces résultats renforcent une nouvelle voie d’action pour lutter contre la progression de la MA. L’utilisation de l’APPsα en tant qu’agent thérapeutique pourrait ainsi s’avérer être un élément important dans l’arsenal clinique de ces prochaines années. / One of the main characteristic of Alzheimer’s Disease (AD) is the intracerebral accumulation of the neurotoxic Amyloid β peptide (Aβ) either as oligomeric or aggregated forms known as the amyloid plaques. This peptide is produced via the Amyloid Precursor Protein (APP) processing following the amyloidogenic pathway, pathological pathway overactivated in AD. Most of the research performed during the last 25 years focused on pathogenic consequences of this dysregulation, deprioritizing the understanding of the APP physiological functions. Nonetheless, numerous studies show that these physiological functions might be mediated via APP soluble forms (APPs). In the physiological APP processing pathway, the non-amyloidogenic pathway, APP is cleaved by the α secretase, releasing the APPsα which display neuroprotective and synaptotrophic properties, essential for brain normal functions. In the context of AD, the amyloidogenic pathway overactivation leads to APPsβ overproduction at the expense of APPsα. Therefore, AD harmful consequences could be due to the decrease of APPsα concentration associated with an increase of APPsβ. My thesis project aimed to characterize mnemonic and functional properties following the overexpression of these two soluble forms of APP and their therapeutic potential in AD. We firstly overexpressed APPsα in hippocampal neurons of APP/PS1ΔE9 mice, animal model of AD, which display cognitive and synaptic deficits. The continual expression of APPsα, mediated via AAV viruses, enabled restoration of spatial memory, long-term potentiation and dendritic spines density in the hippocampus. This phenotypic rescue was accompanied with the decrease of both Aβ levels and amyloid plaques. This might be due to the activation of microglia, cell type able to internalize and degrade Aβ. In a second hand, I studied the involvement of APPsβ in AD, which remains poorly known. Its overexpression in APP/PS1ΔE9 did not induce neither LTP nor spatial memory restoration. However, APPsβ injection lead to the decrease of Aβ levels without reducing amyloid plaques. This default might be due to the lack of microglial activation. In conclusion, my thesis work show that, unlike APPsβ, APPsα overexpression might overcome the AD inevitable evolution by reducing synaptic and memory alterations, typical of AD. These results reinforce a new way of treatment to cope with AD progression. The use of APPsα as therapeutic agent might be an important tool for future AD therapies.

Die Alzheimer Krankheit ist die häufigste Altersdemenz. Ein spezifisches pathologisches Merkmal der Alzheimer Krankheit ist die Amyloid-Ablagerung im Gehirn. Die Hauptkomponente der so genannten Amyloid-Plaques ist das Amyloid beta-Peptid (A-beta). A-beta entsteht durch sequenzielle proteolytische Spaltung aus einem membrangebundenen Vorläuferprotein, dem beta-APP (betaamyloid precursor protein). Die kürzlich identifizierte beta-Sekretase (BACE, beta-site APPcleaving enzyme) generiert den Schnitt am N-Terminus von A-beta. Es entsteht ein C-terminales, membrangebundenes beta-APP-Fragment, das beta-APP-CTF. Beta-APP-CTF ist das direkte Substrat für die gamma-Sekretase, die innerhalb der Membrandomäne schneidet, wodurch A-beta freigesetzt wird. In der vorliegenden Arbeit kann erstmalig gezeigt werden, dass BACE auf dem sekretorischen Transportweg aus dem Endoplasmatischen Retikulum (ER), über den Golgi-Apparat zur Zelloberfläche transportiert wird. Auf dem Transport wird BACE durch N-Glycosylierung und Propeptidabspaltung posttranslational modifiziert. BACE wird im ER N-glycosyliert und die mannosereichen Zucker werden auf dem Transport durch den Golgi-Apparat in Endoglycosidase H resistente Zucker des komplexen Typs modifiziert. Die Propeptidabspaltung, durch Furin oder furinähnliche Propeptidkonvertasen, findet unmittelbar vor dem Aufbau der komplexen Zucker statt. Ferner konnte gezeigt werden, dass der Transport von BACE die A-beta-Entstehung limitieren kann. In polarisierten Madin-Darby canine kidney (MDCK) Zellen wird BACE überwiegend zur apikalen Plasmamembran transportiert und damit entgegengesetzt zu seinem Substrat beta-APP. Der gegensätzliche Transport von BACE und beta-APP begrenzt die A-beta Entstehung. Wird der apikale Transport von beta-APP durch Deletion seines basolateralen Sortierungssignals erhöht, entsteht vermehrt A-beta. Der differenzielle Transport von BACE und beta-APP könnte ein Hinweis darauf sein, dass beta-APP nicht das physiologische Substrat von BACE ist. / Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is caused by complex N-glycosylation. The mature form of BACE is resistant to endoglycosidase H treatment; this indicates that BACE traffics through the Golgi. Furthermore the mature form of BACE does not contain the pro-peptide anymore. Pro-BACE is predominantly located within the endoplasmic reticulum. Pro-peptide cleavage occurs immediately before full maturation by furin or a furin-like proprotein convertase. Moreover traffic of BACE can limit A-beta generation. In the well established model system of polarized Madin-Darby canine kidney (MDCK) cells, the majority of BACE is sorted to the apical domain. Interestingly it has been shown previously that the substrate of BACE, beta-APP is transported to the basolateral surface of MCDK cells. Therefore, substantial amounts of BACE are targeted away from beta-APP to a non-amyloidogenic compartment, a cellular mechanism that limits A-beta generation. Upon deletion of the basolateral sorting signal of beta-APP, apically missorted beta-APP is processed by BACE. The differential targeting of BACE and its substrate beta-APP suggest that beta-APP might not be the major physiological substrate of BACE.