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A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition

Published on May 1, 2019in Biological Psychiatry 11.50
· DOI :10.1016/j.biopsych.2019.04.026
Darrell Sawmiller13
Estimated H-index: 13
,
Ahsan Habib27
Estimated H-index: 27
+ 8 AuthorsJun Tan55
Estimated H-index: 55
Cite
Abstract
Abstract Background The ɛ4 isoform of apolipoprotein E (apoE4) is a major genetic risk factor for the development of sporadic Alzheimer’s disease (AD), and its modification has been an intense focus for treatment of AD during recent years. Methods We investigated the binding of apoE, a peptide corresponding to its low-density lipoprotein receptor binding domain (amino acids 133–152; ApoEp), and modified ApoEp to amyloid precursor protein (APP) and their effects on amyloid-β (Aβ) production in cultured cells. Having discovered a peptide (6KApoEp) that blocks the interaction of apoE with N-terminal APP, we investigated the effects of this peptide and ApoEp on AD-like pathology and behavioral impairment in 3XTg-AD and 5XFAD transgenic mice. Results ApoE and ApoEp, but not truncated apoE lacking the low-density lipoprotein receptor binding domain, physically interacted with N-terminal APP and thereby mediated Aβ production. Interestingly, the addition of 6 lysine residues to the N-terminus of ApoEp (6KApoEp) directly inhibited apoE binding to N-terminal APP and markedly limited apoE- and ApoEp-mediated Aβ generation, presumably through decreasing APP cellular membrane trafficking and p44/42 mitogen-activated protein kinase phosphorylation. Moreover, while promoting apoE interaction with APP by ApoEp exacerbated Aβ and tau brain pathologies in 3XTg-AD mice, disrupting this interaction by 6KApoEp ameliorated cerebral Aβ and tau pathologies, neuronal apoptosis, synaptic loss, and hippocampal-dependent learning and memory impairment in 5XFAD mice without altering cholesterol, low-density lipoprotein receptor, and apoE expression levels. Conclusions These data suggest that disrupting apoE interaction with N-terminal APP may be a novel disease-modifying therapeutic strategy for AD.
  • References (49)
  • Citations (1)
Cite
References49
Newest
Published on Apr 1, 2019in Molecular Neurobiology 4.59
Md. Sahab Uddin7
Estimated H-index: 7
(SEU: Southeast University),
Md. Tanvir Kabir2
Estimated H-index: 2
(BRACU: BRAC University)
+ 3 AuthorsGhulam Md Ashraf15
Estimated H-index: 15
(KAU: King Abdulaziz University)
Alzheimer’s disease (AD) is an immutable neurodegenerative disease featured by the two hallmark brain pathologies that are the extracellular amyloid s (As) and intraneuronal tau protein. People carrying the APOE4 allele are at high risk of AD concerning the ones carrying the e3 allele, while the e2 allele abates risk. ApoE isoforms exert a central role in controlling the transport of brain lipid, neuronal signaling, mitochondrial function, glucose metabolism, and neuroinflammation. Regardless of...
Published on Jul 1, 2018in Molecular Neurobiology 4.59
Simone Eggert13
Estimated H-index: 13
(TUK: Kaiserslautern University of Technology),
Carolin Thomas2
Estimated H-index: 2
(TUK: Kaiserslautern University of Technology)
+ 1 AuthorsGuido Hermey16
Estimated H-index: 16
(UHH: University of Hamburg)
The amyloid precursor protein (APP), one key player in Alzheimer’s disease (AD), is extensively processed by different proteases. This leads to the generation of diverging fragments including the amyloid β (Aβ) peptide, which accumulates in brains of AD patients. Subcellular trafficking of APP is an important aspect for its proteolytic conversion, since the various secretases which cleave APP are located in different cellular compartments. As a consequence, altered subcellular targeting of APP i...
Published on May 1, 2018in Nature Medicine 30.64
Chengzhong Wang3
Estimated H-index: 3
(UCSF: University of California, San Francisco),
Ramsey Najm1
Estimated H-index: 1
(UCSF: University of California, San Francisco)
+ 10 AuthorsZachary A. Miller18
Estimated H-index: 18
(UCSF: University of California, San Francisco)
Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of a...
Published on Feb 1, 2018in Biological Psychiatry 11.50
Na Zhao10
Estimated H-index: 10
(Mayo Clinic),
Chia-Chen Liu22
Estimated H-index: 22
(Mayo Clinic)
+ 1 AuthorsGuojun D Bu71
Estimated H-index: 71
(Ha Tai: Xiamen University)
Abstract Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the e4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not ...
Published on Oct 1, 2017in Journal of Neurochemistry 4.87
Lucas J. Sosa7
Estimated H-index: 7
(National University of Cordoba),
Alfredo Cáceres46
Estimated H-index: 46
(National University of Cordoba)
+ 3 AuthorsAlfredo Lorenzo18
Estimated H-index: 18
(National University of Cordoba)
The amyloid precursor protein (APP) is a type I transmembrane glycoprotein better known for its participation in the physiopathology of Alzheimer disease as the source of the beta amyloid fragment. However, the physiological functions of the full length protein and its proteolytic fragments have remained elusive. APP was first described as a cell-surface receptor; nevertheless, increasing evidence highlighted APP as a cell adhesion molecule (CAM). In this review, we will focus on the current kno...
Published on Sep 1, 2017in Nature 43.07
Yang Shi84
Estimated H-index: 84
,
Kaoru Yamada11
Estimated H-index: 11
+ 30 AuthorsJulio C. Rojas14
Estimated H-index: 14
ApoE4 exacerbates tau pathogenesis, neuroinflammation and tau-mediated neurodegeneration independently of brain amyloid-β pathology, and exerts a ‘toxic’ gain of function whereas its absence is protective.
Published on Sep 1, 2017in Progress in Neurobiology 10.66
Hassan Bukhari4
Estimated H-index: 4
(RUB: Ruhr University Bochum),
Annika Glotzbach2
Estimated H-index: 2
(RUB: Ruhr University Bochum)
+ 3 AuthorsT. Müller25
Estimated H-index: 25
(LMU: Ludwig Maximilian University of Munich)
Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease with tens of millions of people affected worldwide. The pathogenesis is still poorly understood and various therapeutical approaches targeting the amyloid β (Aβ) peptide, a product of the amyloidogenic cleavage of the amyloid precursor protein (APP), failed. Moreover, a couple of studies critically questioned the relevance of Aβ in the pathogenesis of AD. Thus, new ideas need to be studied and one highly interesting h...
Published on Apr 1, 2017in Journal of Neuroscience Research 4.14
Ahsan Habib27
Estimated H-index: 27
(USF: University of South Florida),
Darrell Sawmiller13
Estimated H-index: 13
(USF: University of South Florida),
Jun Tan55
Estimated H-index: 55
(USF: University of South Florida)
Soluble amyloid precursor protein α (sAPPα), a secreted proteolytic fragment of nonamyloidogenic amyloid precursor protein (APP) processing, is known for numerous neuroprotective functions. These functions include but are not limited to proliferation, neuroprotection, synaptic plasticity, memory formation, neurogenesis, and neuritogenesis in cell culture and animal models. In addition, sAPPα influences amyloid-β (Aβ) production by direct modulation of APP β-secretase proteolysis as well as Aβ-re...
Published on Apr 1, 2017in Heliyon
Darrell Sawmiller13
Estimated H-index: 13
(USF: University of South Florida),
Song Li11
Estimated H-index: 11
(USF: University of South Florida)
+ 8 AuthorsPaula C. Bickford54
Estimated H-index: 54
(USF: University of South Florida)
Abstract Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is linked to oxidative stress, altered amyloid precursor protein (APP) proteolysis, tau hyperphosphorylation and the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT). A growing body of evidence suggests that mitochondrial dysfunction can be a key promoter of all of these pathologies and predicts that restoration of mitochondrial function might be a potential therapeutic strategy for AD. Therefore...
Published on Jan 31, 2017in Frontiers in Molecular Neuroscience 3.72
Philip F. Copenhaver16
Estimated H-index: 16
(OHSU: Oregon Health & Science University),
Donat Kögel37
Estimated H-index: 37
(Goethe University Frankfurt)
Following the discovery that the Amyloid Precursor Protein (APP) is the source of β-amyloid peptides (Aβ) that accumulate in Alzheimer’s disease (AD), structural analyses suggested that the holoprotein resembles a transmembrane receptor. Initial studies using reconstituted membranes demonstrated that APP can directly interact with the heterotrimeric G protein Gαo (but not other G proteins) via an evolutionarily G protein-binding motif in its cytoplasmic domain. Subsequent investigations in cell ...
Cited By1
Newest
Published in bioRxiv
Bikash Ranjan Sahoo8
Estimated H-index: 8
(UM: University of Michigan),
Michael E. Bekier3
Estimated H-index: 3
(UM: University of Michigan)
+ -3 AuthorsAyyalusamy Ramamoorthy66
Estimated H-index: 66
(UM: University of Michigan)
Apolipoproteins are involved in pathological conditions of Alzheimer disease (AD), truncated apolipoprotein fragments and beta-amyloid (Abeta) peptides coexist as neurotoxic heteromers within the plaques. Therefore, it is important to investigate these complexes at the molecular level to better understand their properties and roles in the pathology of AD. Here, we present a mechanistic insight into such heteromerization using a structurally homologue apolipoprotein fragment of apoA-I (4F) comple...
Published on Aug 1, 2019in Biological Psychiatry 11.50
Huntington Potter50
Estimated H-index: 50
(University of Colorado Denver),
Heidi J. Chial7
Estimated H-index: 7
(University of Colorado Denver)