Identification of an amino-terminal fragment of apolipoprotein E4 that localizes to neurofibrillary tangles of the Alzheimer's disease brain

Rohn, Troy T.; Catlin, Lindsey W.; Coonse, Kendra G.; Habig, Jeffrey W.

doi:10.1016/j.brainres.2012.08.003

Cited by 36 publications

(57 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our data indicate potent neuritogenic activity of the apoE 25 kDa fragment that is very similar to that of full-length apoE. There is previous evidence that apoE fragments (and apoE-mimetic peptides) are biologically active as they regulate neuronal signalling (39, 40) and control either neurodegenerative or neuroprotective pathways and anti-inflammatory pathways, depending on the fragments analysed (15,18,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). Some of these previous reports focused on a potentially toxic apoE C-terminal truncated 30 kDa fragment and other shorter thrombolytic and synthetic fragments, which were suggested to be present in the "insoluble fractions" of human AD brain homogenates.…”

Section: Discussionmentioning

confidence: 97%

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Muñoz

Liu

Ruberu

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Apolipoprotein-E (apoE) is a glycoprotein highly expressed in the brain, where it appears to play a role in lipid transport, b-amyloid clearance, and neuronal signaling. ApoE proteolytic fragments are also present in the brain, but the enzymes responsible for apoE fragmentation are unknown, and the biological activity of specific apoE fragments remains to be determined. Here we utilised SK-N-SH neuroblastoma cells differentiated into neurons with all-trans retinoic acid (ATRA) to study extracellular apoE proteolysis. ApoE fragments were detectable in culture supernatants after 3 days, and their levels were increased for up to 9 days in the presence of ATRA. The concentration of apoE fragments was positively correlated with levels of the neuronal maturation markers (PSD95 and SMI32). The most abundant apoE fragments were 25 kDa and 28 kDa N-terminal fragments that both contained sialylated glycosylation and bound to heparin. We detected apoE fragments only in the extracellular milieu and not in cell lysates, suggesting that an extracellular protease contributes to apoE fragmentation.Of note, siRNA-mediated knockdown of high-temperature requirement serine peptidase A1 (HtrA1) and a specific HtrA1 inhibitor reduced apoE 25 kDa fragment formation by 41% and 86%, respectively. Recombinant 25-kDa fragment apoE and full-length apoE both stimulated neuritogenesis in vitro, increasing neuroblastoma neurite growth by more than 2-fold over a 6-day period. This study provides a cellular model for assessing apoE proteolysis, indicates that HtrA1 regulates apoE 25-kDa fragment formation under physiological conditions, and reveals a new neurotrophic function for the apoE 25-kDa fragment. ________________________________________

show abstract

Section: Discussionmentioning

confidence: 97%

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Muñoz

Liu

Ruberu

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…These data support the hypothesis that intraneuronal proteolytic cleavage of apoE4 could promote the neuropathology and neurodegeneration in AD brains. Supporting a role of proteolytic cleavage of apoE4 are studies demonstrating the presence of apoE4 fragments (14–20 kDa) in the AD brain [34,40–42]. …”

Section: Proteolysis Of Apoe4 As a Mechanism Underlying Pathogenesmentioning

confidence: 99%

“…Thus, the C -terminal domain of apoE4 has been implicated in binding to beta-amyloid and is localized to plaques [36,40,42]. On the other hand, the N -terminal domain preferentially localizes within NFTs [34].…”

Section: Proteolysis Of Apoe4 As a Mechanism Underlying Pathogenesmentioning

confidence: 99%

“…We recently confirmed the specific localization of the N -terminal domain of apoE4 to NFTs in the AD brain by synthesizing a site-directed antibody to a putative cleavage site within apoE4 at position D172. This antibody, which detects only the N -terminal fragment of apoE4 localized exclusively within NFTs of the AD brain [42] (Figure 1). The high susceptibility of apoE4 to proteolytic cleavage may be the driving force behind the enhanced risk for AD in individuals who are either heterozygous or homozygous for the APOE4 allele.…”

Section: Proteolysis Of Apoe4 As a Mechanism Underlying Pathogenesmentioning

confidence: 99%

See 1 more Smart Citation

Proteolytic Cleavage of Apolipoprotein E4 as the Keystone for the Heightened Risk Associated with Alzheimer’s Disease

Rohn

2013

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%–80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to undergo proteolytic cleavage generating N- and C-terminal fragments. The purpose of this review will be to examine the mechanisms by which apoE4 contributes to AD pathogenesis focusing on the potential loss or gain of function that may occur following cleavage of the full-length protein. In this context, a discussion of whether targeting apoE4 therapeutically is a rationale approach to treating this disease will be assessed.

show abstract

“…To determine if this site within apoE is cleaved by proteases in the AD brain, we developed and characterized a site-directed neoepitope antibody directed towards the amino-terminal fragment that would be generated following cleavage at D172. Application of this antibody, in situ , revealed specific localization within NFTs that co-localized with PHF-1 in the AD brain with a preference of localization in those AD cases with either the 3/4 or 4/4 APOE genotypes [7]. The purpose of the present study was to examine whether amino-terminal fragments of apoE can be documented in Pick's disease.…”

Section: Introductionmentioning

confidence: 91%

Immunolocalization of an Amino-Terminal Fragment of Apolipoprotein E in the Pick's Disease Brain

et al. 2013

Self Cite

View full text Add to dashboard Cite

Although the risk factor for apolipoprotein E (apoE) polymorphism in Alzheimer's disease (AD) has been well described, the role that apoE plays in other neurodegenerative diseases, including Pick's disease, is not well established. To examine a possible role of apoE in Pick's disease, an immunohistochemical analysis was performed utilizing a novel site-directed antibody that is specific for an amino-terminal fragment of apoE. Application of this antibody, termed the amino-terminal apoE cleavage fragment (nApoECF) antibody, consistently labeled Pick bodies within area CA1 of the hippocampus in 4 of the 5 cases examined. Co-localization of the nApoECF antibody with PHF-1, a general marker for Pick bodies, as well as with an antibody to caspase-cleaved tau (TauC3) was evident within the hippocampus. While staining of the nApoECF antibody was robust in area CA1, little co-localization with PHF-1 in Pick bodies within the dentate gyrus was observed. A quantitative analysis indicated that approximately 86% of the Pick bodies identified in area CA1 labeled with the nApoECF antibody. The presence of truncated apoE within Pick bodies suggests a broader role of apoE beyond AD and raises the question as to whether this protein contributes to pathogenesis associated with Pick's disease.

show abstract

Identification of an amino-terminal fragment of apolipoprotein E4 that localizes to neurofibrillary tangles of the Alzheimer's disease brain

Cited by 36 publications

References 17 publications

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Proteolytic Cleavage of Apolipoprotein E4 as the Keystone for the Heightened Risk Associated with Alzheimer’s Disease

Immunolocalization of an Amino-Terminal Fragment of Apolipoprotein E in the Pick's Disease Brain

Contact Info

Product

Resources

About