Amyloid Precursor Protein Regulates Brain Apolipoprotein E and Cholesterol Metabolism through Lipoprotein Receptor LRP1

Liu, Qiang; Zerbinatti, Celina; Zhang, Juan; Hoe, Hyang Sook; Wang, Baiping; Cole, Sarah L.; Herz, Joachim; Muglia, Louis J.; Bu, Guojun

doi:10.1016/j.neuron.2007.08.008

Cited by 333 publications

(299 citation statements)

References 60 publications

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“…In contrast, overexpression of the LDLR in the brain decreases apoE levels, reflecting an increased metabolism of apoE (Kim et al 2009b). Similarly, conditional deletion of the Lrp1 gene in mouse forebrain neurons increases apoE levels (Liu et al 2007) and overexpression of a functional LRP1 minireceptor in mouse brain decreases brain apoE levels (Zerbinatti et al 2006). Although both LDLR and LRP1 play roles in brain apoE/lipoprotein metabolism, there are important differences between them.…”

Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

“…First, whereas LRP1 is highly expressed in neurons and to a lesser degree in glia, LDLR is more prominently expressed in glia than neurons (Rebeck et al 1993;Rapp et al 2006). Second, deletion of the Lrp1 gene in mouse forebrain neurons reduces brain cholesterol levels (Liu et al 2007), whereas cholesterol levels in Ldlr knockout mice are unchanged (Fryer et al 2005a). Third, apoE/lipoprotein particles secreted by astrocytes have higher affinity for LDLR than LRP1 (Fryer et al 2005a), whereas recombinant apoE (Narita et al 2002), apoE-enriched lipoprotein particles (Kowal et al 1990), and CSF-isolated HDL particles (Fagan et al 1996) bind more avidly to LRP1.…”

Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

“…1). Some of these receptors, such as LDLR and LRP1, influence apoE levels (Fryer et al 2005a;Liu et al 2007). Others, such as Apoer2 and VLDLR, although apoE receptors, are also receptors for other ligands such as the neuromodulatory signaling protein Reelin, which plays an important role in neurodevelopment and synpatic function.…”

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confidence: 99%

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Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

675

602

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Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

Section: Lrp1 and Ldlr In Cellular And Brain Ab Metabolismmentioning

confidence: 99%

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Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

675

602

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“…In fact, Fe65 or Fe65-AICD complex interact with nuclear proteins such as Tip60, SET, CP2/LSF (13-15) and experimental evidence indicated that they could be involved in transcription activation (16)(17)(18)(19)(20). However, several studies raised the question of the specificity of this regulation; in particular, De Strooper and colleagues (21) demonstrated that ␥-secretase inhibitors, suppression of presenilins or APP/APLP2 do not induce any significant change in the expression levels of several candidate genes, whereas Fe65 appears to have a rather nonspecific effect on transcription.…”

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confidence: 99%

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

Stante

Minopoli

Passaro

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Fe65 is a binding partner of the Alzheimer's ␤-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites.Alzheimer ͉ APP ͉ DNA repair T he ␤-amyloid peptides, main constituents of senile plaques of Alzheimer disease (AD), derive from the proteolytic processing of a type I membrane protein, known as ␤-amyloid precursor protein (APP) (1). APP functions are not completely understood, and this knowledge could contribute, at least in principle, to the understanding of AD. Possible cues to study the functions of APP could emerge from the analysis of proteins interacting with the short APP cytosolic domain. Several reports indicated that this cytodomain interacts, among the others, with the Fe65 protein (2-4). The latter has the characteristics of an adaptor protein, whose distinctive traits are 3 protein-protein interaction domains, 1 WW and 2 PTB (PhosphoTyrosine Binding) domains (4). The PTB domain located in the C-terminal part of the protein (PTB2) interacts with the cytodomain of APP and of the 2 related proteins APLP1 and APLP2. Similarly, Fe65 has also been found associated with APP intracellular domain (AICD) (5), which is generated, together with the ␤-amyloid peptides, upon the cleavage of APP by secretases (1).Experimental evidence from cultured cells suggested 2 possible functions of Fe65, one depending on its presence in the cytosol and another one on its nuclear localization. APP-Fe65 complexes are present in neuronal growth cones (6) and regulate cell motility (7). Considering that Fe65 WW domain interacts with Mena (8) and APP also with mDab1 (9), these findings support the hypothesis that the APP-Fe65 complex is involved in actin-based membrane remodeling, neurite growth and/or synaptic plasticity. The analysis of the phenotypes of APP/APLP1/APLP2 triple KO ...

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“…The targets that have been reported to be up-regulated included the metastasis suppressor KAI1/CD82 (60,61), the tumor suppressor TP53 (62), the A␤-degrading enzyme neprilysin (NEP) (42,(62)(63)(64), the endoplasmic reticulum stress and unfolded protein response gene CHOP/DDIT3 (C/EBP homologous protein/ DNA damage-inducible transcript 3) (65), and sonic hedgehog receptor Patched (PTCH1) (66). In contrast, down-regulated targets included the epidermal growth factor receptor (EGFR) (67) and the low density lipoprotein receptorrelated protein 1 (LRP1) (68). Although not formally defined as direct targets, the glycogen synthase kinase3␤ (GSK3␤) (59,69,70), APP (59) itself, and BACE1 (59) are considered AICD-regulated genes.…”

Section: Aicd A␤42 and Tau Interactions With Dnamentioning

confidence: 99%

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

Multhaup

Huber

Buée

et al. 2015

Journal of Biological Chemistry

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Alzheimer disease (AD) 2 is the most common form of dementia and a leading cause of death. Amyloid-␤ (A␤) peptides of varying length (30 -51 amino acid residues) are produced by the sequential, proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases (1, 2). In the healthy brain, these protein fragments are normally degraded and eliminated. In the AD brain, the 42-amino acid peptide (A␤42) is prone to form aggregated amyloid oligomers, which are believed to contribute to plaque formation and cognitive decline (3-6).The ␥-secretase also liberates an intracellular fragment called AICD composed of up to 50 residues depending on N-terminal variations (7-9). The first identification of the APP intracellular fragment (AICD) and its detection in brain tissue (8) immediately suggested that it has transcriptional activity, like the Notch intracellular domain (NICD). Whether amyloid A␤ represents a biologically inert bypass product of APP processing or can harbor its own function is a leading question in the AD field. A␤ is potentially toxic depending on its biophysical state (10). Equimolar amounts of the A␤ peptides and the C-terminal fragment AICD are derived from the ␤-C-terminal fragment C99 (11), which represents the APP fragment generated by the initial APP cleavage by ␤-secretase (Fig. 1).A seminal discovery concerning the transcriptional regulatory function of the APP cytoplasmic tail was the observation of its complex formation with Fe65 and the histone acetyltransferase Tip60 and transcriptional activity in reporter gene assays (12). Transactivation of transcription requires ␥-secretase activity and nuclear translocation of Fe65 but not of AICD under these assay conditions (13). However, other studies detected AICD in transcriptional complexes on promoters of target genes using ChIP (see below).In addition, there is evidence that soluble APP fragments (sAPP) of the ectodomain can modulate gene transcription in stimulating downstream signaling through unknown sAPP receptor(s) (14). Accumulation of intracellular A␤ species in neuronal cells before plaque formation leading to concomitant loss of MAP2 expression suggested that A␤ may affect expression or turnover of other proteins (15-17). However, it was not clarified whether this occurs at the transcriptional or translational level.Using a variety of techniques, the recently detected uptake of A␤ peptides into the nuclei of cultured cells (as well as in vivo) revealed that A␤42 possesses unique modulatory activity (18). Direct evidence for the presence of (i) nuclear A␤42 in wildtype animals, (ii) the increased level of nuclear A␤42 in APPoverexpressing animals, and (iii) the detection of nuclear A␤ in quantities comparable with other transcription factors imply a certain biological relevance.The second major hallmark of AD pathology is the presence of neurofibrillary tangles and is associated with intracellular Tau aggregates called neurofibrillary tangles and with modified Tau (19). Although the neuronal Tau (tubulin-associated unit...

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Amyloid Precursor Protein Regulates Brain Apolipoprotein E and Cholesterol Metabolism through Lipoprotein Receptor LRP1

Cited by 333 publications

References 60 publications

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

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