The Asparaginyl Endopeptidase Legumain: An Emerging Therapeutic Target and Potential Biomarker for Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is incurable dementia closely associated with aging. Most cases of AD are sporadic, and very few are inherited; the pathogenesis of sporadic AD is complex and remains to be elucidated. The asparaginyl endopeptidase (AEP) or legumain is the only recognized cysteine protease that specifically hydrolyzes peptide bonds after asparagine residues in mammals. The expression level of AEPs in healthy brains is far lower than that of peripheral organs. Recently, growing evidence has indicated that aging may upregulate and overactivate brain AEPs. The overactivation of AEPs drives the onset of AD through cleaving tau and amyloid precursor proteins (APP), and SET, an inhibitor of protein phosphatase 2A (PP2A). The AEP-mediated cleavage of these peptides enhances amyloidosis, promotes tau hyperphosphorylation, and ultimately induces neurodegeneration and cognitive impairment. Upregulated AEPs and related deleterious reactions constitute upstream events of amyloid/tau toxicity in the brain, and represent early pathological changes in AD. Thus, upregulated AEPs are an emerging drug target for disease modification and a potential biomarker for predicting preclinical AD. However, the presence of the blood–brain barrier greatly hinders establishing body-fluid-based methods to measure brain AEPs. Research on AEP-activity-based imaging probes and our recent work suggest that the live brain imaging of AEPs could be used to evaluate its predictive efficacy as an AD biomarker. To advance translational research in this area, AEP imaging probes applicable to human brain and AEP inhibitors with good druggability are urgently needed.

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An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.

Ye Zhang, Kenian Chen, Steven A Sloan … (2014)

The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase. This dataset will provide a powerful new resource for understanding the development and function of the brain. To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://web.stanford.edu/group/barres_lab/brain_rnaseq.html) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain. Copyright © 2014 the authors 0270-6474/14/3411929-19$15.00/0.

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Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

Fangda Leng, Paul Edison (2021)

Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60-70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD.

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2022 Alzheimer's disease facts and figures

(2022)

This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, use and costs of care, and the overall impact on family caregivers, the dementia workforce and society. The Special Report discusses consumers' and primary care physicians' perspectives on awareness, diagnosis and treatment of mild cognitive impairment (MCI), including MCI due to Alzheimer's disease. An estimated 6.5 million Americans age 65 and older are living with Alzheimer's dementia today. This number could grow to 13.8 million by 2060 barring the development of medical breakthroughs to prevent, slow or cure AD. Official death certificates recorded 121,499 deaths from AD in 2019, the latest year for which data are available. Alzheimer's disease was officially listed as the sixth-leading cause of death in the United States in 2019 and the seventh-leading cause of death in 2020 and 2021, when COVID-19 entered the ranks of the top ten causes of death. Alzheimer's remains the fifth-leading cause of death among Americans age 65 and older. Between 2000 and 2019, deaths from stroke, heart disease and HIV decreased, whereas reported deaths from AD increased more than 145%. More than 11 million family members and other unpaid caregivers provided an estimated 16 billion hours of care to people with Alzheimer's or other dementias in 2021. These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver. Unpaid dementia caregiving was valued at $271.6 billion in 2021. Its costs, however, extend to family caregivers' increased risk for emotional distress and negative mental and physical health outcomes - costs that have been aggravated by COVID-19. Members of the dementia care workforce have also been affected by COVID-19. As essential care workers, some have opted to change jobs to protect their own health and the health of their families. However, this occurs at a time when more members of the dementia care workforce are needed. Average per-person Medicare payments for services to beneficiaries age 65 and older with AD or other dementias are almost three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 22 times as great. Total payments in 2022 for health care, long-term care and hospice services for people age 65 and older with dementia are estimated to be $321 billion. A recent survey commissioned by the Alzheimer's Association revealed several barriers to consumers' understanding of MCI. The survey showed low awareness of MCI among Americans, a reluctance among Americans to see their doctor after noticing MCI symptoms, and persistent challenges for primary care physicians in diagnosing MCI. Survey results indicate the need to improve MCI awareness and diagnosis, especially in underserved communities, and to encourage greater participation in MCI-related clinical trials.