ArticleJournal of the American Chemical Society2016
HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 44 citations in OpenAlex.
- Rare Variants in HTRA1, SGTB, and RBM12 Confer Risk of Atherosclerotic Cardiovascular Disease Independent of Traditional Cardiovascular Risk Factors.Circulation. Genomic and precision medicine · 2025Article
- Exome sequencing of a Portuguese cohort of early-onset Alzheimer's disease implicates the X-linked lysosomal gene GLA.Scientific reports · 2025Article
- HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.Nature communications · 2024Article
- Current Views on Chr10q26 Contribution to Age-Related Macular Degeneration.Advances in experimental medicine and biology · 2023Review
- The emerging role of the HTRA1 protease in brain microvascular disease.Frontiers in dementia · 2023Review
- A multi-hit hypothesis for an APOE4-dependent pathophysiological state.The European journal of neuroscience · 2022Review
- Report of two pedigrees with heterozygous HTRA1 variants-related cerebral small vessel disease and literature review.Molecular genetics & genomic medicine · 2022Review
- Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia.Brain and behavior · 2022Article
- Dissecting the clinical heterogeneity of early-onset Alzheimer's disease.Molecular psychiatry · 2022Review
- An allosteric HTRA1-calpain 2 complex with restricted activation profile.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates.Acta neuropathologica communications · 2022Article
- APP deficiency and HTRA2 modulates PrPBBA advances · 2022Article
- Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer's disease?Therapeutic advances in chronic disease · 2022Review
- Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration.Experimental eye research · 2021Review
- Generation of APOE knock-down SK-N-SH human neuroblastoma cells using CRISPR/Cas9: a novel cellular model relevant to Alzheimer's disease research.Bioscience reports · 2021Article
- Astrocytic expression of the Alzheimer's disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models.Scientific reports · 2021Article
- Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration.Frontiers in neuroscience · 2021Review
- Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer's disease.Molecular neurodegeneration · 2020Article
- The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer's Disease.Frontiers in immunology · 2020Review
- Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Apolipoprotein E (ApoE) belongs to a large class of proteins that solubilize lipids for physiological transport. Humans have three different APOE alleles, APOE ε2, APOE ε3, and APOE ε4, and genetic studies identified ApoE4 as the strongest genetic risk factor for Alzheimer's disease (AD). People who are homozygous for ApoE4 (i.e., ApoE4/E4) are an order of magnitude more likely to develop late-onset AD (LOAD) than ApoE3/E3 carriers. Several differences between ApoE3 and ApoE4 may contribute to AD including the observation that ApoE4 is degraded to a greater extent than ApoE3 in the human brain. Experiments with high-temperature requirement serine peptidase A1 (HtrA1), which is found in the nervous system, demonstrate that HtrA1 is an allele-selective ApoE-degrading enzyme that degrades ApoE4 more quickly than ApoE3. This activity is specific to HtrA1, as similar assays with HtrA2 showed minimal ApoE4 proteolysis and trypsin had no preference between ApoE4 and ApoE3. HtrA1 has also been reported to cleave the tau protein (Tau) and the amyloid protein precursor (APP) to hinder the formation of toxic amyloid deposits associated with AD. Competition assays with ApoE4, ApoE3, and Tau revealed that ApoE4 inhibits Tau degradation. Thus, the identification of ApoE4 as an in vitro HtrA1 substrate suggests a potential biochemical mechanism that links ApoE4 regulation of AD proteins such as Tau.
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