Book Review: Alzheimer's Disease Research: What has guided research so far and why it is high time for a paradigm shift (Christian Behl. Springer Nature, Switzerland, 2023) 661 pp.

This is a review of a recently published book entitled 'Alzheimer's Disease Research: What has guided research so far and why it is high time for a paradigm shift' by Christian Behl, a leading contributor to the field of Alzheimer disease over the last three decades. It presents a personal viewpoint on the historical developments in dementia research and therapeutics from its early beginnings through to the current day. The conflicting hypotheses, the therapeutic trials, the successes and the failures of the vast research infrastructure devoted to dissecting the aberrant pathways underlying the inexorable progression of this ultimately fatal neurodegenerative disease are discussed. It is based, among others, on numerous personal discussions of the author with other leading researchers in the field, and thus gives this (hi)story of Alzheimer research a personal touch and spotlight on controversies that distinguishes it from other books in the field.

Angiotensin-converting enzyme 2 (ACE2): Two decades of revelations and re-evaluation.

Angiotensin-converting enzyme-2, or ACE2, is primarily a zinc-dependent peptidase and ectoenzyme expressed in numerous cell types and functioning as a counterbalance to ACE in the renin-angiotensin system. It was discovered 21 years ago more than 40 years after the discovery of ACE itself. Its primary physiological activity is believed to be in the conversion of angiotensin II to the vasodilatory angiotensin-(1-7) acting through the Mas receptor. As such it has been implicated in numerous pathological conditions, largely in a protective mode which has led to the search for ACE2 activatory mechanisms. ACE2 has a diverse substrate specificity allowing its participation in multiple peptide pathways. It also regulates aspects of amino acid transport through its homology with a membrane protein, collectrin. It also serves as a viral receptor for the SARS virus, and subsequently SARS-CoV2, driving the current COVID-19 pandemic. ACE2 therefore provides a therapeutic target for the treatment of COVID and understanding the biological events following viral binding can provide insight into the multiple pathologies caused by the virus, particularly inflammatory and vascular. In part this may relate to the ability of ACE2, like ACE, to be shed from the cell membrane. The shed form of ACE2 (sACE2) may be a factor in determining susceptibility to certain COVID pathologies. Hence, for just over 20 years, ACE2 has provided numerous surprises in the field of vasoactive peptides with, no doubt, more to come but it is its central role in COVID pathology that is producing the current intense interest in its biology.

Effect of Global Brain Ischemia on Amyloid Precursor Protein Metabolism and Expression of Amyloid-Degrading Enzymes in Rat Cortex: Role in Pathogenesis of Alzheimer's Disease.

The incidence of Alzheimer's disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic amyloid species and brain damage. The effects of global 15-min ischemia and 120-min reperfusion on the levels of expression of the amyloid precursor protein (APP) and its processing were investigated in the brain cortex (Cx) of male Wistar rats. Additionally, the levels of expression of the amyloid-degrading enzymes neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), and insulin-degrading enzyme (IDE), as well as of some markers of oxidative damage were assessed. It was shown that the APP mRNA and protein levels in the rat Cx were significantly increased after the ischemic insult. Protein levels of the soluble APP fragments, especially of sAPPß produced by ß-secretase, (BACE-1) and the levels of BACE-1 mRNA and protein expression itself were also increased after ischemia. The protein levels of APP and BACE-1 in the Cx returned to the control values after 120-min reperfusion. The levels of NEP and ECE-1 mRNA also decreased after ischemia, which correlated with the decreased protein levels of these enzymes. However, we have not observed any changes in the protein levels of insulin-degrading enzyme. Contents of the markers of oxidative damage (di-tyrosine and lysine conjugates with lipid peroxidation products) were also increased after ischemia. The obtained data suggest that ischemia shifts APP processing towards the amyloidogenic ß-secretase pathway and accumulation of the neurotoxic Aß peptide as well as triggers oxidative stress in the cells. These results are discussed in the context of the role of stress and ischemia in initiation and progression of AD.

ACE2, a multifunctional protein - from cardiovascular regulation to COVID-19.

This Editorial, written by Guest Editors Professor Michael Bader, Professor Anthony J. Turner and Dr Natalia Alenina, proudly introduces the Clinical Science-themed collection on angiotensin-converting enzyme 2 (ACE2), a multifunctional protein - from cardiovascular regulation to coronavirus disease 2019 (COVID-19).

Discovery and characterization of ACE2 - a 20-year journey of surprises from vasopeptidase to COVID-19.

Angiotensin-converting enzyme (ACE) is a zinc membrane metallopeptidase that plays a key role in regulating vasoactive peptide levels and hence cardiovascular activity through its conversion of angiotensin I (Ang I) to Ang II and its metabolism of bradykinin. The discovery of its homologue, ACE2, 20 years ago has led to intensive comparisons of these two enzymes revealing surprising structural, catalytic and functional distinctions between them. ACE2 plays multiple roles not only as a vasopeptidase but also as a regulator of amino acid transport and serendipitously as a viral receptor, mediating the cellular entry of the coronaviruses causing severe acute respiratory syndrome (SARS) and, very recently, COVID-19. Catalytically, ACE2 functions as a monocarboxypeptidase principally converting the vasoconstrictor angiotensin II to the vasodilatory peptide Ang-(1-7) thereby counterbalancing the action of ACE on the renin-angiotensin system (RAS) and providing a cardioprotective role. Unlike ACE, ACE2 does not metabolise bradykinin nor is it inhibited by classical ACE inhibitors. However, it does convert a number of other regulatory peptides in vitro and in vivo. Interest in ACE2 biology and its potential as a possible therapeutic target has surged in recent months as the COVID-19 pandemic rages worldwide. This review highlights the surprising discoveries of ACE2 biology during the last 20 years, its distinctions from classical ACE and the therapeutic opportunities arising from its multiple biological roles.

Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2.

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

The origins and early history of neurochemistry and its societies.

At the 2017 joint meeting of the International Society for Neurochemistry (ISN) and the European Society for Neurochemistry, 150 years of neurochemistry - the 50th anniversary of ISN, 40 years of European Society for Neurochemistry, and 60 years of the Journal of Neurochemistry (JNC) - was celebrated with a historical symposium that explored the foundations of neurochemical societies, key international figures in the discipline of neurochemistry, and the pre-eminent role of the JNC. The foundations of neurochemistry were laid in Europe, notably France and Germany, in the late 18th and early 19th centuries. Neurochemists in the United Kingdom made globally relevant contributions before and after the Second World War, and Swedish contributions were especially prominent in the 1950s and 1960s. As neurochemistry is a truly international branch of neuroscience, the important contributions of neurochemists in the Americas and the Asia-Pacific were also recognized, as were the seminal roles of the American, Asia-Pacific, and Japanese Societies of Neurochemistry. Although ISN was only formed in 1967, earlier international meetings in Europe and the Americas reflected the growing recognition of the importance of chemistry and biochemistry for understanding and responding to the pathophysiology of clinical conditions and diseases of the central and peripheral nervous systems. JNC was first published in 1956, but the ISN only assumed complete ownership of the journal under tempestuous circumstances in 1970. The ISN-JNC interface and the sterling work of the JNC Editors has meant that the income generated by the journal has allowed the ISN Council to implement diverse programs for supporting neurochemistry internationally, including sustaining regional neurochemical societies, and supporting neurochemists in the developing world and schools of neurochemistry.

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy.

Targeting the amyloid-ß (Aß) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aß is central to the disease process. Most attention has focused on the biosynthesis of Aß from its precursor protein through the successive actions of the ß- and γ-secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aß are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid-degrading enzymes (ADEs) and by a variety of transport processes. The development of late-onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin-degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up-regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aß clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration.

This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory. Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus. On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation. This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions, in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-ß peptide (Aß). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aß clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration. Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aß accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy.

The malleable brain: plasticity of neural circuits and behavior - a review from students to students.

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on page 788. Cover Image for this issue: doi: 10.1111/jnc.13815.

Role of Ageing and Oxidative Stress in Regulation of Amyloid-Degrading Enzymes and Development of Neurodegeneration.

The accumulation of cerebral amyloid ßpeptide (Aß) is a key precipitating factor for neuronal cell death in Alzheimer's Disease (AD). However, brain Aß levels are modifiable since there is a balance between its formation from the Amyloid Precursor Protein (APP) and its removal by clearance mechanisms, which can be either through proteolysis or by protein binding and subsequent transport). Among the major enzymes degrading brain Aß are several zinc-proteases: neprilysin (NEP), its homologues NEP2 and the Endothelin Converting Enzymes (ECE-1 and -2) and also the Insulin-Degrading Enzyme (IDE). During the ageing process, and under certain pathological conditions (e.g. ischemia and stroke), the expression and activity of these enzymes decline, which leads to a deficit of Aß clearance and its accumulation in the brain. Some of these changes in the enzyme properties are due to their reduced expression and/or structural modification by reactive oxygen species. In this review paper we shall discuss some mechanisms of regulation of Amyloid-Degrading Enzymes (ADEs) and possible therapeutic approaches which might prevent their decline with age and after pathology.

Reflections on 60 years of publication of the Journal of Neurochemistry.

This review reflects on the origins, development, publishing trends, and scientific directions of the Journal of Neurochemistry over its 60 year lifespan as seen by key contributors to the Journal's production. The Journal first appeared in May 1956 with just two issues published in that inaugural year. By 1963, it appeared monthly and, by 2002, 24 hard copy issues were published yearly. In 2014, the Journal became online only. For much of its time, the Journal was managed through two separate editorial offices each with their respective Chief Editor (the 'Western' and 'Eastern' hemispheres). The Journal was restructured to operate through a single editorial office and Editor-in-Chief from 2013. Scientifically, the Journal progressed through distinct scientific eras with the first two decades generally centered around developments in methodology followed by a period when publications delved deeper into underlying mechanisms. By the late 1980s, the Journal had entered the age of genetics and beyond, with an increasing focus on neurodegenerative diseases. Reviews have played a regular part in the success of J Neurochem with focused special and virtual issues being a highlight of recent years. Today, 60 years and onwards, J Neurochem continues to be a leading source of top-quality, original and review articles in neuroscience. We look forward to its continued success at the forefront of neurochemistry in the decades to come. This article celebrates 60 years of publication of Journal of Neurochemistry including personal reminiscences from some of the Chief Editors, past and present, as well as input from some of the key contributors to the Journal over this period. We highlight the scientific, technological, and publishing developments along the way, with reference to key papers published in the Journal. The support of the Journal toward the aims and objectives of the International Society for Neurochemistry (ISN) is also emphasized. This article is part of the 60th Anniversary special issue.

A Learned Society's Perspective on Publishing.

Scientific journals that are owned by a learned society, like the Journal of Neurochemistry (JNC), which is owned by the International Society for Neurochemistry (ISN), benefit the scientific community in that a large proportion of the income is returned to support the scientific mission of the Society. The income generated by the JNC enables the ISN to organize conferences as a platform for members and non-members alike to share their research, supporting researchers particularly in developing countries by travel grants and other funds, and promoting education in student schools. These direct benefits and initiatives for ISN members and non-members distinguish a society journal from pure commerce. However, the world of scholarly publishing is changing rapidly. Open access models have challenged the business model of traditional journal subscription and hence provided free access to publicly funded scientific research. In these models, the manuscript authors pay a publication cost after peer review and acceptance of the manuscript. Over the last decade, numerous new open access journals have been launched and traditional subscription journals have started to offer open access (hybrid journals). However, open access journals follow the general scheme that, of all participating parties, the publisher receives the highest financial benefit. The income is generated by researchers whose positions and research are mostly financed by taxpayers' or funders' money, and by reviewers and editors, who frequently are not reimbursed. Last but not least, the authors pay for the publication of their work after a rigorous and sometimes painful review process. JNC itself has an open access option, at a significantly reduced cost for Society members as an additional benefit. This article provides first-hand insights from two former Editors-in-Chief, Kunihiko Suzuki and Leslie Iversen, about the history of JNC's ownership and about the difficulties and battles fought along the way to its current success and reputation. Scientific journals that are owned by a learned society, like the Journal of Neurochemistry (JNC) which is owned by the International Society for Neurochemistry (ISN), benefit the scientific community in that a large proportion of the income is returned to support the scientific mission of the Society. The income generated by the JNC enables the ISN to organize conferences as a platform for members and non-members alike to share their research, supporting researchers particularly in developing countries by travel grants and other funds, and to promote education in student schools. These direct benefits and initiatives for ISN members and non-members distinguish a society journal from pure commerce. However, the world of scholarly publishing is changing rapidly. Open access models have challenged the business model of traditional journal subscription and hence provide free access to publicly funded scientific research. In these models, the manuscript authors pay a publication cost after peer review and acceptance of the manuscript. Over the last decade, numerous new open access journals have been launched and traditional subscription journals have started to offer open access (hybrid journals). However, open access journals pertain to the general scheme that, of all participating parties, the publisher receives the highest financial benefit. The income is generated by researchers whose positions and research are mostly financed by tax payers' or funders' money, reviewers and editors, who frequently are not reimbursed. Last but not least, the authors pay for the publication of their work after a rigorous and sometimes painful review process. JNC itself has an open access option, at a significantly reduced cost for Society members as an additional benefit. This article provides first-hand insights from a long-standing Editor-in-Chief, Kunihiko Suzuki, about the history of JNC's ownership and about difficulties and battles fought on the way to its current success and reputation today. This article is part of the 60th Anniversary special issue.

AChE and the amyloid precursor protein (APP) - Cross-talk in Alzheimer's disease.

The amyloid precursor protein (APP) and acetylcholinesterase (AChE) are multi-faceted proteins with a wide range of vital functions, both crucially linked with the pathogenesis of Alzheimer's disease (AD). APP is the precursor of the Aß peptide, the pathological agent in AD, while AChE is linked to its pathogenesis either by increasing cholinergic deficit or exacerbating Aß fibril formation and toxicity. As such, both proteins are the main targets in AD therapeutics with AChE inhibitors being currently the only clinically available AD drugs. In our studies we have demonstrated an important inter-relation in functioning of these proteins. Both can be released from the cell membrane and we have shown that AChE shedding involves a metalloproteinase-mediated mechanism which, like the α-secretase dependent cleavage of APP, is stimulated by cholinergic agonists. Overexpression of the neuronal specific isoform APP695 in neuronal cells substantially decreased levels of the AChE mRNA, protein and catalytic activity accompanied by a similar decrease in mRNA levels of the AChE membrane anchor, PRiMA (proline rich membrane anchor). We further established that this regulation does not involve APP processing and its intracellular domain (AICD) but requires the E1 region of APP, specifically its copper-binding domain. On the contrary, siRNA knock-down of APP in cholinergic SN56 cells resulted in a significant upregulation of AChE mRNA levels. Hence APP may influence AChE physiology while released AChE may regulate amyloidogenesis through multiple mechanisms suggesting novel therapeutic targets.

New Insights into Epigenetic and Pharmacological Regulation of Amyloid-Degrading Enzymes.

Currently, deficit of amyloid ß-peptide (Aß) clearance from the brain is considered as one of the possible causes of amyloid accumulation and neuronal death in the sporadic form of Alzheimer's disease (AD). Aß clearance can involve either specific proteases present in the brain or Aß-binding/transport proteins. Among amyloid-degrading enzymes the most intensively studied are neprilysin (NEP) and insulin-degrading enzyme (IDE). Since ageing and development of brain pathologies is often accompanied by a deficit in the levels of expression and activity of these enzymes in the brain, there is an urgent need to understand the mechanisms involved in their regulation. We have recently reported that NEP and also an Aß-transport protein, transthyretin are epigenetically co-regulated by the APP intracellular domain (AICD) and this regulation depends on the cell type and APP695 isoform expression in a process that can be regulated by the tyrosine kinase inhibitor, Gleevec. We have now extended our work and shown that, unlike NEP, another amyloid-degrading enzyme, IDE, is not related to over-expression of APP695 in neuroblastoma SH-SY5Y cells but is up-regulated by APP751 and APP770 isoforms independently of AICD but correlating with reduced HDAC1 binding to its promoter. Studying the effect of the nuclear retinoid X receptor agonist, bexarotene, on NEP and IDE expression, we have found that both enzymes can be up-regulated by this compound but this mechanism is not APP-isoform specific and does not involve AICD but, on the contrary, affects HDAC1 occupancy on the NEP gene promoter. These new insights into the mechanisms of NEP and IDE regulation suggest possible pharmacological targets in developing AD therapies.

Hypoxia Affects Neprilysin Expression Through Caspase Activation and an APP Intracellular Domain-dependent Mechanism.

While gene mutations in the amyloid precursor protein (APP) and the presenilins lead to an accumulation of the amyloid ß-peptide (Aß) in the brain causing neurodegeneration and familial Alzheimer's disease (AD), over 95% of all AD cases are sporadic. Despite the pathologies being indistinguishable, relatively little is known about the mechanisms affecting generation of Aß in the sporadic cases. Vascular disorders such as ischaemia and stroke are well established risk factors for the development of neurodegenerative diseases and systemic hypoxic episodes have been shown to increase Aß production and accumulation. We have previously shown that hypoxia causes a significant decrease in the expression of the major Aß-degrading enzyme neprilysin (NEP) which might deregulate Aß clearance. Aß itself is derived from the transmembrane APP along with several other biologically active metabolites including the C-terminal fragment (CTF) termed the APP intracellular domain (AICD), which regulates the expression of NEP and some other genes in neuronal cells. Here we show that in hypoxia there is a significantly increased expression of caspase-3, 8, and 9 in human neuroblastoma NB7 cells, which can degrade AICD. Using chromatin immunoprecipitation we have revealed that there was also a reduction of AICD bound to the NEP promoter region which underlies the decreased expression and activity of the enzyme under hypoxic conditions. Incubation of the cells with a caspase-3 inhibitor Z-DEVD-FMK could rescue the effect of hypoxia on NEP activity protecting the levels of AICD capable of binding the NEP promoter. These data suggest that activation of caspases might play an important role in regulation of NEP levels in the brain under pathological conditions such as hypoxia and ischaemia leading to a deficit of Aß clearance and increasing the risk of development of AD.

Crystal structure of X-prolyl aminopeptidase from Caenorhabditis elegans: A cytosolic enzyme with a di-nuclear active site.

Eukaryotic aminopeptidase P1 (APP1), also known as X-prolyl aminopeptidase (XPNPEP1) in human tissues, is a cytosolic exopeptidase that preferentially removes amino acids from the N-terminus of peptides possessing a penultimate N-terminal proline residue. The enzyme has an important role in the catabolism of proline containing peptides since peptide bonds adjacent to the imino acid proline are resistant to cleavage by most peptidases. We show that recombinant and catalytically active Caenorhabditis elegans APP-1 is a dimer that uses dinuclear zinc at the active site and, for the first time, we provide structural information for a eukaryotic APP-1 in complex with the inhibitor, apstatin. Our analysis reveals that C. elegans APP-1 shares similar mode of substrate binding and a common catalytic mechanism with other known X-prolyl aminopeptidases.