The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease

Amyloid plaques are defining histopathologic lesions in the brains of Alzheimer's disease (AD) patients and are composed of the amyloid-beta peptide, which is widely considered to play a critical role in the pathogenesis of AD. The β-secretase, or β-site amyloid precursor protein cleaving enzyme 1 (BACE1; also called Asp2, memapsin 2), is the enzyme that initiates the generation of amyloid beta. Consequently, BACE1 is an attractive drug target for lowering cerebral levels of amyloid beta for the treatment or prevention of AD. Much has been learned about BACE1 since its discovery over 10 years ago. In the present article, we review BACE1 properties and characteristics, cell biology, in vivo validation, substrates, therapeutic potential, and inhibitor drug development. Studies relating to the physiological functions of BACE1 and the promise of BACE1 inhibition for AD will also be discussed. We conclude that therapeutic inhibition of BACE1 should be efficacious for AD, although careful titration of the drug dose may be necessary to limit mechanism-based side effects

The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb

<p>Abstract</p> <p>Background</p> <p>The β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), is a prime therapeutic target for lowering cerebral β-amyloid (Aβ) levels in Alzheimer's disease (AD). Clinical development of BACE1 inhibitors is being intensely pursued. However, little is known about the physiological functions of BACE1, and the possibility exists that BACE1 inhibition may cause mechanism-based side effects. Indeed, BACE1^-/-mice exhibit a complex neurological phenotype. Interestingly, BACE1 co-localizes with presynaptic neuronal markers, indicating a role in axons and/or terminals. Moreover, recent studies suggest axon guidance molecules are potential BACE1 substrates. Here, we used a genetic approach to investigate the function of BACE1 in axon guidance of olfactory sensory neurons (OSNs), a well-studied model of axon targeting <it>in vivo</it>.</p> <p>Results</p> <p>We bred BACE1^-/-mice with gene-targeted mice in which GFP is expressed from the loci of two odorant-receptors (ORs), MOR23 and M72, and olfactory marker protein (OMP) to produce offspring that were heterozygous for MOR23-GFP, M72-GFP, or OMP-GFP and were either BACE1^+/+or BACE1^-/-. BACE1^-/-mice had olfactory bulbs (OBs) that were smaller and weighed less than OBs of BACE1^+/+mice. In wild-type mice, BACE1 was present in OSN axon terminals in OB glomeruli. In whole-mount preparations and tissue sections, many OB glomeruli from OMP-GFP; BACE1^-/-mice were malformed compared to wild-type glomeruli. MOR23-GFP; BACE1^-/-mice had an irregular MOR23 glomerulus that was innervated by randomly oriented, poorly fasciculated OSN axons compared to BACE1^+/+mice. Most importantly, M72-GFP; BACE1^-/-mice exhibited M72 OSN axons that were mis-targeted to ectopic glomeruli, indicating impaired axon guidance in BACE1^-/-mice.</p> <p>Conclusions</p> <p>Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in axon guidance. OSNs continually undergo regeneration and hence require ongoing axon guidance. Neurogenesis and the regeneration of neurons and axons occur in other adult populations of peripheral and central neurons that also require axon guidance throughout life. Therefore, BACE1 inhibitors under development for the treatment of AD may potentially cause axon targeting defects in these neuronal populations as well.</p

BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization

<p>Abstract</p> <p>Background</p> <p>BACE1 is a key enzyme in the generation of the Aβ peptide that plays a central role in the pathogenesis of Alzheimer's disease. While BACE1 is an attractive therapeutic target, its normal physiological function remains largely unknown. Examination of BACE1^-/-mice can provide insight into this function and also help anticipate consequences of BACE1 inhibition. Here we report a seizure-susceptibility phenotype that we have identified and characterized in BACE1^-/-mice.</p> <p>Results</p> <p>We find that electroencephalographic recordings reveal epileptiform abnormalities in some BACE1^-/-mice, occasionally including generalized tonic-clonic and absence seizures. In addition, we find that kainic acid injection induces seizures of greater severity in BACE1^-/-mice relative to BACE1^+/+littermates, and causes excitotoxic cell death in a subset of BACE1^-/-mice. This hyperexcitability phenotype is variable and appears to be manifest in approximately 30% of BACE1^-/-mice. Finally, examination of the expression and localization of the voltage-gated sodium channel α-subunit Na_v1.2 reveals no correlation with BACE1 genotype or any measure of seizure susceptibility.</p> <p>Conclusions</p> <p>Our data indicate that BACE1 deficiency predisposes mice to spontaneous and pharmacologically-induced seizure activity. This finding has implications for the development of safe therapeutic strategies for reducing Aβ levels in Alzheimer's disease. Further, we demonstrate that altered sodium channel expression and axonal localization are insufficient to account for the observed effect, warranting investigation of alternative mechanisms.</p

Prion protein interacts with bace1 and differentially regulates its activity towards wild type and swedish mutant amyloid precursor protein

In Alzheimer disease amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the β-secretase BACE1 is the rate-limiting step in the production of Aβ. We have reported previously that the cellular prion protein (PrP(C)) inhibited the action of BACE1 toward human wild type APP (APP(WT)) in cellular models and that the levels of endogenous murine Aβ were significantly increased in PrP(C)-null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation. PrP(C) interacted directly with the prodomain of the immature Golgi-localized form of BACE1. This interaction decreased BACE1 at the cell surface and in endosomes where it preferentially cleaves APP(WT) but increased it in the Golgi where it preferentially cleaves APP with the Swedish mutation (APP(Swe)). In transgenic mice expressing human APP with the Swedish and Indiana familial mutations (APP(Swe,Ind)), PrP(C) deletion had no influence on APP proteolytic processing, Aβ plaque deposition, or levels of soluble Aβ or Aβ oligomers. In cells, although PrP(C) inhibited the action of BACE1 on APP(WT), it did not inhibit BACE1 activity toward APP(Swe). The differential subcellular location of the BACE1 cleavage of APP(Swe) relative to APP(WT) provides an explanation for the failure of PrP(C) deletion to affect Aβ accumulation in APP(Swe,Ind) mice. Thus, although PrP(C) exerts no control on cleavage of APP(Swe) by BACE1, it has a profound influence on the cleavage of APP(WT), suggesting that PrP(C) may be a key protective player against sporadic Alzheimer disease

The effect of stress on the expression of the amyloid precursor protein in rat brain

AbstractThe abnormal processing of the amyloid precursor protein (APP) is a pivotal event in the development of the unique pathology that defines Alzheimer's disease (AD). Stress, and the associated increase in corticosteroids, appear to accelerate brain ageing and may increase vulnerability to Alzheimer's disease via altered APP processing. In this study, rats were repeatedly exposed to an unavoidable stressor, an open elevated platform. Previous studies in this laboratory have shown that a single exposure produces a marked increase in plasma corticosterone levels but animals develop tolerance to this effect between 10 and 20 daily sessions. Twenty-four hours after stress, there was an increase in the ratio of the deglycosylated form of APP in the particulate fraction of the brain, which subsequently habituated after 20 days. The levels of soluble APP (APPs) tended to be lower in the stress groups compared to controls except for a significant increase in the hippocampus after 20 days of platform exposure. Since APPs is reported to have neurotrophic properties, this increased release may represent a neuroprotective response to repeated stress. It is possible that the ability to mount this response decreases with age thus increasing the vulnerability to stress-induced AD-related pathology

Effects of statin therapies on individuals taking antipsychotics: A systematic review

Introduction: Patients with a severe mental illness (SMI) taking antipsychotics may develop side effects such as dyslipidemia. Our objective is to provide an update to a previous systematic review showing statin therapy lowering lipid levels in individuals taking antipsychotics while further identifying changes, if present, in body mass index (BMI), blood pressure or any safety concerns.Methods: In August 2022, we searched MEDLINE, Embase, PsycINFO, PubMed and Cochrane Central Register of Controlled Trials for studies pertaining to the effects of statins on lipid profile measures for those taking first or second generation antipsychotic medications, with a diagnosis related to SMI. Data extraction was performed in a masked duplicate fashion. Based on article type, each study’s risk of bias was assessed using ROBINS-I or RoB-2. The GRADE criteria were used for certainty assessment.Results: Our initial search returned 396 articles, of which six were included. Five (of 6, 83.3%) articles identified significant change between baseline and post-treatment lipids. Of the articles recording blood pressure, BMI or weight and significant safety concerns, no significant changes were found. The certainty assessment for this systematic review is rated moderate. A meta-analysis was not performed.Discussion: Studies continue to demonstrate statin therapy’s utilization in prevention and treatment for dyslipidemia and its related cardiovascular risk through significant reduction in LDL-C. Patients at risk of developing dyslipidemias secondarily to antipsychotic treatment for a SMI should be considered for lipid lowering therapy with a statin. The limited number of studies included and their heterogeneity demonstrates areas for improvement for future research

Description and Characterisation of a Large Array of Sensors Mimicking an Artifical Olfactory Epithelium

Biological olfactory systems show high sensitivity and exquisite discriminatory capacity to odorants. These characteristics are due to hierarchical signal processing of the large numbers of sensory inputs that occurs within the olfactory system. In testing realistic computational models of the olfactory system, large numbers of chemical sensor inputs are required. So far, sensory devices that may serve as model inputs to an artificial olfactory system do not exist. The development of a large scale array of chemical sensors able to mimic the olfactory receptor neurons is described, and these have been characterised in terms of their variability and degree of redundancy. Using this device it is possible to start testing computational hypotheses appropriate to biological chemosensory systems and adapt them to the artificial olfaction

The case for low-level BACE1 inhibition for the prevention of Alzheimer disease

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform ‘go–no-go’ decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention

Working together better for mental health in children and young people during a pandemic: experiences from North Central London during the first wave of COVID-19

Direct risk from infection from COVID-19 for children and young people (CYP) is low, but impact on services, education and mental health (so-called collateral damage) appears to have been more significant. In North Central London (NCL) during the first wave of the pandemic, in response to the needs and demands for adults with COVID-19, general paediatric wards in acute hospitals and some paediatric emergency departments were closed. Paediatric mental health services in NCL mental health services were reconfigured. Here we describe process and lessons learnt from a collaboration between physical and mental health services to provide care for CYP presenting in mental health crisis. Two new ‘hubs’ were created to coordinate crisis presentations in the region and to link community mental health teams with emergency departments. All CYP requiring a paediatric admission in the first wave were diverted to Great Ormond Street Hospital, a specialist children’s hospital in NCL, and a new ward for CYP mental health crisis admissions was created. This brought together a multidisciplinary team of mental health and physical health professionals. The most common reason for admission to the ward was following a suicide attempt (n=17, 43%). Patients were of higher acute mental health complexity than usually admitted to the hospital, with some CYP needing an extended period of assessment. In this review, we describe the challenges and key lessons learnt for the development of this new ward setting that involved such factors as leadership, training and also new governance processes. We also report some personal perspectives from the professionals involved. Our review provides perspective and experience that can inform how CYP with mental health admissions can be managed in paediatric medical settings