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Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer’s disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of...
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... donors or their next of kin provided informed signed consents to the Institute for Memory Impairments and Neurological Disorders for the use of their tissues in research (IRB 2014(IRB - 1526. Case demographics are presented in Table 1 for immunohistochemical studies and Table 2 for Western blot analyses. ...
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Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative disease, currently affecting over 5 million Americans with projections expected to rise as the population ages. The hallmark pathologies of AD are Aβ plaques composed of aggregated beta-amyloid (Aβ), and tau tangles composed of hyperphosphorylated, aggregated tau. These pathol...
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... Several proteases have been suggested to be responsible for ApoE4 cleavage at different sites, including collagenase, matrix metalloproteinas-9 (MMP-9) [25], neuronspecific α-chymotrypsin-like serine protease [26], cathepsin D (the only aspartic protease identified) [27] and high-temperature requirement serine protease A1 (HtrA1) [21]. Some of these enzymes are cytoplasmatic, while others can cleave ApoE4 extracellularly, generating the fragments that are further endocytosed, enter the cytosol and interact with mitochondria, intracellular proteins or translocate to the nucleus [11]. ...
... Fragments with 14 to 20 kDa have been found in the brain of AD patients carrying the APOE ε4 allele [27], including ApoE4 N-terminal fragment [25] and C-terminal truncated forms [28], and in higher levels than in age-and sex-matched controls [29]. Additionally, it has been observed that ApoE4 fragmentation occurs in a brain regiondependent way, preferentially in the neocortex and hippocampus of neuron-specific enolase (NSE)-ApoE4 transgenic mice (mice expressing ApoE4 under the control of NSE promoter), being both areas very susceptible to AD-related neurodegeneration [30], as previously described in this review. ...
... For example, some studies in N2a cells demonstrated that ApoE4 N-terminal fragments (1-272 aa (amino acids)) interact with mitochondria and may possibly impact on mitochondrial function and cell viability [29], as well as Aβ deposition [21] and ADrelated tau pathology [11]. Other authors demonstrated that N-terminal fragments of ApoE4 (1-151 aa) translocate to the nucleus and act as a transcription factor (Figure 1), promoting AD pathogenesis [25], but also being taken up by microglia and contributing to cell death [27]. Figure 1. ...
APOE e4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer’s disease (AD), expressed in 40–65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, the exact mechanism underlying ApoE4 impact on AD progression is unclear, while no effective therapies are available for this highly debilitating neurodegenerative disorder. This review describes the current knowledge of ApoE4 interaction with mitochondria, causing mitochondrial dysfunction and neurotoxicity, associated with increased mitochondrial Ca2+ and reactive oxygen species (ROS) levels, and it effects on mitochondrial dynamics, namely fusion and fission, and mitophagy. Moreover, ApoE4 translocates to the nucleus, regulating the expression of genes involved in aging, Aβ production, inflammation and apoptosis, potentially linked to AD pathogenesis. Thus, novel therapeutical targets can be envisaged to counteract the effects induced by ApoE4 in AD brain.
... We recently examined the role of an amino-terminal fragment of ApoE4 previously identified in the human AD brain utilizing cultured BV2 microglia cells. Our findings demonstrated that exogenous application of this amino-terminal fragment of ApoE4 (nApoE4 ) in microglial cells resulted in uptake of nApoE4 , trafficking to microglial nuclei, and the expression of numerous genes associated with inflammation [16][17][18]. To expand on this work, the current study employed an in vivo zebrafish system to study the fragment in a complex organism. ...
... The goal of the present study was not to employ zebrafish as a model of AD per se, but to test whether a risk factor associated with AD could lead to toxicity or other potential negative consequences in an in vivo model. In this manner, the use of wild-type zebrafish embryos was used to extend our previous in vitro findings in transformed cells [16][17][18]. Our results demonstrate that exogenous treatment of zebrafish embryos with nApoE4 1-151 led to an increase in toxicity and other morphological abnormalities. ...
... Sections were then kept in the dark at 4˚C until used for confocal imaging. Following labeling, confocal assessment of the localization of nApoE4 1-151 in neuronal cell populations was as previously described [18]. All images and z-stacks generated were obtained using Zeiss Microscope, LSM 510 Meta confocal imaging system (Carl Zeiss, Oberkochen, Germany) and processed using Zen blue edition (Carl Zeiss, Göttingen, Germany). ...
Although the increased risk of developing sporadic Alzheimer's disease (AD) associated with the inheritance of the apolipoprotein E4 (APOE4) allele is well characterized, the molecular underpinnings of how ApoE4 imparts risk remains unknown. Enhanced proteolysis of the ApoE4 protein with a toxic-gain of function has been suggested and a 17 kDa amino-terminal ApoE4 fragment (nApoE41-151) has been identified in post-mortem human AD frontal cortex sections. Recently, we demonstrated in vitro, exogenous treatment of nApoE41-151 in BV2 microglial cells leads to uptake, trafficking to the nucleus and increased expression of genes associated with cell toxicity and inflammation. In the present study, we extend these findings to zebrafish (Danio rerio), an in vivo model system to assess the toxicity of nApoE41-151. Exogenous treatment of nApoE41-151 to 24-hour post-fertilization for 24 hours resulted in significant mortality. In addition, developmental abnormalities were observed following treatment with nApoE41-151 including improper folding of the hindbrain, delay in ear development, deformed yolk sac, enlarged cardiac cavity, and significantly lower heart rates. A similar nApoE31-151 fragment that differs by a single amino acid change (C>R) at position 112 had no effects on these parameters under identical treatment conditions. Decreased presence of pigmentation was noted for both nApoE31-151- and nApoE41-151-treated larvae compared with controls. Behaviorally, touch-evoked responses to stimulus were negatively impacted by treatment with nApoE41-151 but did not reach statistical significance. Additionally, triple-labeling confocal microscopy not only confirmed the nuclear localization of the nApoE41-151 fragment within neuronal populations following exogenous treatment, but also identified the presence of tau pathology, one of the hallmark features of AD. Collectively, these in vivo data demonstrating toxicity as well as sublethal effects on organ and tissue development support a novel pathophysiological function of this AD associated-risk factor.
... The altered structure may, for example, expose regions of the amino acid sequence that are normally hidden in full-length APOE, potentially creating binding sites in the APOE fragments for interactions with other molecules that are not present in full-length APOE. In addition to the mitochondrial interaction and localization of APOE fragments, APOE fragments were also shown to be localized in the nucleus, indicating potential activity as a transcription factor, as observed with a 17-kDa APOE fragment [43,44]. Most studies on APOE fragments conclude that the detected APOE fragments have adverse effects, except for a study in which an extracellular 25-kDa APOE fragment was found to act neurotrophically and to stimulate neurite growth in cultured neurons [38]. ...
Human apolipoprotein E (APOE), originally known for its role in lipid metabolism, is polymorphic with three major allele forms, namely, APOEε2, APOEε3, and APOEε4, leading to three different human APOE isoforms. The ε4 allele is a genetic risk factor for Alzheimer’s disease (AD); therefore, the vast majority of APOE research focuses on its role in AD pathology. However, there is increasing evidence for other functions of APOE through the involvement in other biological processes such as transcriptional regulation, mitochondrial metabolism, immune response, and responsiveness to dietary factors. Therefore, the aim of this review is to provide an overview of the potential novel functions of APOE and their characterization. The detection of APOE in various cell organelles points to previously unrecognized roles in mitochondria and others, although it is actually considered a secretory protein. Furthermore, numerous interactions of APOE with other proteins have been detected, providing indications for new metabolic pathways involving APOE. The present review summarizes the current evidence on APOE beyond its original role in lipid metabolism, to change the perspective and encourage novel approaches to future research on APOE and its isoform-dependent role in the cellular metabolism.
... For example, cytosolic APOE has been recognized as a critical lipid transporter involved in lipid metabolism [62][63][64] . Further studies have revealed the nuclear localization of APOE in human fibroblasts and human hepatic and glioblastoma cell lines 35,[65][66][67] , supporting the role of nuclear APOE as a transcriptional regulator to modulate the expression of metabolic genes at their promoters, including SIRT1, APOD and PP2A 34,65,67 . However, little has been shown about the mechanism of APOE in regulating human stem cell senescence. ...
Apolipoprotein E (APOE) is a component of lipoprotein particles that function in the homeostasis of cholesterol and other lipids. Although APOE is genetically associated with human longevity and Alzheimer’s disease, its mechanistic role in aging is largely unknown. Here, we used human genetic, stress-induced and physiological cellular aging models to explore APOE-driven processes in stem cell homeostasis and aging. We report that in aged human mesenchymal progenitor cells (MPCs), APOE accumulation is a driver for cellular senescence. By contrast, CRISPR–Cas9-mediated deletion of APOE endows human MPCs with resistance to cellular senescence. Mechanistically, we discovered that APOE functions as a destabilizer for heterochromatin. Specifically, increased APOE leads to the degradation of nuclear lamina proteins and a heterochromatin-associated protein KRAB-associated protein 1 via the autophagy–lysosomal pathway, thereby disrupting heterochromatin and causing senescence. Altogether, our findings uncover a role of APOE as an epigenetic mediator of senescence and provide potential targets to ameliorate aging-related diseases. Apolipoprotein E (APOE) is a lipoprotein particle component and is genetically linked to human longevity and Alzheimer’s disease; however, the mechanisms that link APOE and aging are incompletely understood. Here, Zhao et al. show that APOE drives cellular senescence in aged human mesenchymal progenitor cells by destabilizing heterochromatin.
... In the BV2 mouse microglial cell line, the 17 kDa fragment has been reported to promote cell death. 178 It has been reported that intracellular Aβ 1-42 accumulation is stimulated by the 19 kDa fragment, which produces reactive oxygen species (ROS) in the SK-N-SH human neuroblastoma cell line. 74,179 In this cell line and SW-1783 human astrocytoma cells, the 21 kDa fragment has been also reported to promote MMP9/TIMP1 imbalance, by stimulating IL-1β and reducing IL-10 levels. ...
Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE ( APOE) have a fourfold greater risk of developing Alzheimer’s disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction.
... We have recently identified a 151 amino-terminal fragment of ApoE4 (E4 fragment) that is generated following cleavage of the full-length ApoE4 (FL-ApoE4) and localizes within the nuclei of microglia cells in the human AD brain [5]. In addition, we have shown that exogenous treatment of BV2 microglia cells with this E4 fragment leads to the uptake and trafficking to the nucleus and cytotoxicity [5]. ...
... We have recently identified a 151 amino-terminal fragment of ApoE4 (E4 fragment) that is generated following cleavage of the full-length ApoE4 (FL-ApoE4) and localizes within the nuclei of microglia cells in the human AD brain [5]. In addition, we have shown that exogenous treatment of BV2 microglia cells with this E4 fragment leads to the uptake and trafficking to the nucleus and cytotoxicity [5]. A transcriptome analyses following exogenous treatment with the E4 fragment resulted in the up regulation of almost 4,000 genes, with 20 of these genes up regulated 182-to 715-fold. ...
... As shown in Figure 1, strong nuclear localization of the nApoE4 1-151 was evident ( Figure 1C), while localization of full-length ApoE4 appeared to be more cytoplasmic although some nuclear staining was also evident ( Figure 1E). These results confirm our previous findings in vitro [5]. ...
The apolipoprotein E4 (APOE4) allele represents the single greatest risk factor for late-onset Alzheimer's disease (AD) and accumulating evidence suggests that fragmentation with a toxic-gain of function may be a key molecular step associated with this risk. Recently, we demonstrated strong immunoreactivity of a 151 amino-terminal fragment of apoE4 (E4-fragment) within the nucleus of microglia in the human AD brain. In vitro, this fragment led to toxicity and activation of inflammatory processes in BV2 microglia cells. Additionally, a transcriptome analysis following exogenous treatment of BV2 microglia cells with this E4 fragment led to a > 2-fold up regulation of 1,608 genes, with many genes playing a role in inflammation and microglia activation. To extend these findings, we here report a similar transcriptome analysis in BV2 microglia cells following treatment with full-length ApoE4 (FL-ApoE4). The results indicated that full-length ApoE4 had a very small effect on gene expression compared to the fragment. Only 48 differentially expressed genes (DEGs) were identified (p < 0.05, and greater than 2-fold change). A gene ontology analysis of these DEGs indicated that they are not involved in inflammatory and activation processes, in contrast to the genes up regulated by the E4-fragment. In addition, genes that showed a negative fold-change upon FL-E4 treatment typically showed a strong positive fold-change upon treatment with the fragment (Pearson's r = -0.7). Taken together, these results support the hypothesis that a key step in the conversion of microglia to an activated phenotype is proteolytic cleavage of FL-ApoE4. Therefore, the neutralization of this amino-terminal fragment of ApoE4, specifically, may serve as an important therapeutic strategy in the treatment of AD.
... These contrasting conformational properties between APOE isoforms have consequences for synaptic function Love et al., 2006;Qiu et al., 2003), glial cell function (Vitek et al., 2009;Zhu et al., 2012), blood-brain barrier (Box 1) integrity (Bell et al., 2012;Montagne et al., 2020;Nishitsuji et al., 2011), generation and differentiation of newborn neurons (Levi and Michaelson, 2007;Nathan et al., 1995), and distribution of APOE in the brain (Achariyar et al., 2016). The following section explores the multifunctional nature of APOE in the brain, explaining why differential effects of APOE isoforms extend to cell survival (Andrews-Zwilling et al., 2010;Hayashi et al., 2007;Zhao et al., 2017), glucose delivery to cells (Wu et al., 2018), formation of toxic fragments (Huang et al., 2001;Love et al., 2017) and gene expression patterns (Lin et al., 2018) (Fig. 1B). ...
The importance of apolipoprotein E ( APOE ) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the biological factors linking APOE to sex hormones, drawing on supportive findings from rodent models to identify major mechanistic themes underlying the exacerbation of LOAD-associated neurodegeneration and pathology in the female brain. Additionally, we list sex-by-genotype interactions identified across neurodegenerative diseases, proposing APOE variants as a shared etiology for sex differences in the manifestation of these diseases. Finally, we present recent advancements in ‘omics’ technologies, which provide a new platform for more in-depth investigations of how dysregulation of this gene affects the development and progression of neurodegenerative diseases. Collectively, the evidence summarized in this Review highlights the interplay between APOE and sex as a key factor in the etiology of LOAD and other age-related neurodegenerative diseases. We emphasize the importance of careful examination of sex as a contributing factor in studying the underpinning genetics of neurodegenerative diseases in general, but particularly for LOAD.
... Thus, ApoE4 is proteolyzed more readily than ApoE3, and fragments of ApoE4 are more prevalent in the brains of AD patients (Huang et al., 2001;Rohn et al., 2012;Rohn, 2013). Recently, we extended these findings by demonstrating that an amino-terminal fragment of ApoE4 (nApoE4 1−151 ) generated following cleavage of fulllength ApoE4 by extracellular cellular proteases including MMP-9 is taken up by microglia, targets to the nucleus, and can induce cytotoxicity (Love et al., 2017). We also found the presence of this fragment in the nucleus of microglia in both E4/E4 and E3/E3 cases of postmortem AD brain sections (Love et al., 2017). ...
... Recently, we extended these findings by demonstrating that an amino-terminal fragment of ApoE4 (nApoE4 1−151 ) generated following cleavage of fulllength ApoE4 by extracellular cellular proteases including MMP-9 is taken up by microglia, targets to the nucleus, and can induce cytotoxicity (Love et al., 2017). We also found the presence of this fragment in the nucleus of microglia in both E4/E4 and E3/E3 cases of postmortem AD brain sections (Love et al., 2017). Our hypothesis is that nApoE4 1−151 acts as a transcription factor leading to the expression of genes that promote microglia activation (Pollock et al., 2019). ...
... Our previous findings have demonstrated the nuclear localization of amino-terminal fragments of apoE4 within microglia both in vivo, in the AD brain and in vitro following exogenous treatment of BV2 microglia cells (Love et al., 2017). To confirm and extend these findings, we exogenously treated BV2 microglia cells with both nApoE3 1−151 and nApoE4 1−151 fragments, which differ by a single amino acid (C→R). ...
Despite the fact that harboring the apolipoprotein E4 (APOE4) allele represents the single greatest risk factor for late-onset Alzheimer’s disease (AD), the exact mechanism by which ApoE4 contributes to disease progression remains unknown. Recently, we demonstrated that a 151 amino-terminal fragment of ApoE4 (nApoE41–151) localizes within the nucleus of microglia in the human AD brain and traffics to the nucleus causing toxicity in BV2 microglia cells. In the present study, we examined in detail what genes may be affected following treatment by nApoE41–151. Transcriptome analyses in BV2 microglial cells following sublethal treatment with nApoE41–151 revealed the upregulation of almost 4,000 genes, with 20 of these genes upregulated 182- to 715-fold compared to untreated control cells. The majority of these 20 genes play a role in the immune response and polarization toward microglial M1 activation. As a control, an identical nApoE31–151 fragment that differed by a single amino acid at position 112 (Cys→Arg) was tested and produced a similar albeit lower level of upregulation of an identical set of genes. In this manner, enriched pathways upregulated by nApoE31–151 and nApoE41–151 following exogenous treatment included Toll receptor signaling, chemokine/cytokine signaling and apoptosis signaling. There were unique genes differentially expressed by at least two-fold for either fragment. For nApoE31–151, these included 16 times as many genes, many of which are involved in physiological functions within microglia. For nApoE41–151, on the other hand the number genes uniquely upregulated was significantly lower, with many of the top upregulated genes having unknown functions. Taken together, our results suggest that while nApoE31–151 may serve a more physiological role in microglia, nApoE41–151 may activate genes that contribute to disease inflammation associated with AD. These data support the hypothesis that the link between harboring the APOE4 allele and dementia risk could be enhanced inflammation through activation of microglia.
... The ApoE4 fragment is endocytosed by BV2 microglia in vitro, is translocated to the nucleus, where it subsequently causes the death of microglia. The ApoE3derived fragment remains in the cytoplasm and causes no toxicity (Love et al. 2017). Chronic activation of the cytokines MMP-9, IL-1β, and TNF-α contributes to AD pathogenesis and pathophysiology. ...
Alzheimer's disease (AD) is a very common cause of dementia in the elderly. It is characterized by progressive amnesia and accretions of neurofibrillary tangles (NFTs) of neurons and senile plaques in the neuropil. After aging, the inheritance of the apolipoprotein E (ApoE) epsilon 4 (ε4) allele is the greatest risk factor for late-onset AD. The ApoE protein is the translated product of the ApoE gene. This protein undergoes proteolysis, and the resulting fragments colocalize with neurofibrillary tangles and amyloid plaques, and for that matter may be involved in AD onset and/or progression. Previous studies have reported the pathogenic potential of various ApoE fragments in AD pathophysiology. However, the pathways activated by the fragments are not fully understood. In this review, ApoE fragments obtained from post-mortem brains and body fluids, cerebrospinal fluid (CSF) and plasma, are discussed. Additionally, current knowledge about the process of fragmentation is summarized. Finally, the mechanisms by which these fragments are involved in AD pathogenesis and pathophysiology are discussed.
... The difference in the apoE fragmentation pattern observed in apoE3 and apoE4 brains leads us to question the biological roles of the different apoE fragments and whether they have a relationship with AD pathogenesis (Table 2). Specific apoE fragments have been directly linked with the formation of Aβ plaques, tau hyperphosphorylation/NFT formation, and the initiation of neurodegeneration [35,40,[46][47][48]]. An 18 kDa N-terminal fragment (1-172 aa) of apoE4 was found within NFT of AD patients [49], however the presence of this fragment in cerebrospinal fluid or plasma did not correlate with AD or APOE genotype [50]. ...
... Other studies have focused on the role of different N-terminal apoE4 fragments ranging from 17 to 22 kDa. Love et al. suggested the extracellular proteases collagenase and matrix metalloprotease-9 produce a 17 kDa apoE 1-151 fragment and in the apoE4 background the fragment traffics to the nucleus of BV2 mouse microglial cells increasing cell death [48]. Dafnis et al. showed in the SK-N-SH human neuroblastoma cell line that the 19 kDa N-terminal fragment of apoE4 (apoE 1-165) stimulated the intracellular accumulation of Aβ42, generating ROS, but this effect was absent with apoE3 or with the 21 kDa fragment (apoE 1-185) [65,66]. ...
... ApoE is expressed in the brain mainly by astrocytes, however the evidence suggests that neurons rather than astrocytes express the enzymes leading to apoE fragmentation. A number of enzymes have been proposed [68]) promoting neurotoxicity [36], mitochondrial dysfunction [53], tau phosphorylation and NFT-like inclusions [47], neurodegeneration [40], cell death [48] or suppressing microglial activation [56] (Fig. 2). However, our recent study has found a protective function of the apoE 25 kDa fragment that is more prevalent in apoE3 than apoE4 brains [43]. ...
Alzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases. It has been known for decades that the APOE ɛ4 allele is the most significant genetic risk factor for late-onset AD and yet its precise role in the disease remains unclear. The APOE gene encodes apolipoprotein E (apoE), a 35 kDa glycoprotein highly expressed in the brain. There are three different isoforms: apoE3 is the most common allele in the population, whilst apoE2 decreases, and apoE4 increases AD risk. ApoE has numerous functions that affect neuronal and non-neuronal cells, thus how it contributes to disease onset and progression is hotly debated. The apoE4 isoform has been linked to the accumulation of both of the major pathological hallmarks of AD, amyloid plaques containing amyloid β peptides, and neurofibrillary tangles containing hyperphosphorylated tau protein, as well as other hallmarks of the disease, including inflammation and oxidative stress. Numerous studies have shown that apoE undergoes fragmentation in the human brain, and that the fragmentation pattern varies between isoforms. It was previously shown that apoE4 has neurotoxic functions, however recent data has also identified a neuroprotective role for the apoE N-terminal 25 kDa fragment, which is more prevalent in apoE3 individuals. The ability of the apoE 25 kDa fragment to promote neurite outgrowth was recently demonstrated and this suggests there is a potential loss of neuroprotection in apoE4 individuals in addition to the previously described gain of toxic function for specific apoE4 fragments. Here we review the enzymes proposed to be responsible for apoE fragmentation, the specific functions of different apoE fragments and their possible links with AD.
