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Cited by 104Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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APP Function and Lipids: A Bidirectional Link

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Grimm, Marcus O. W., Mett, Janine, Grimm, Heike S., Hartmann, Tobias·2017·Frontiers in Molecular Neuroscience
DOI 10.3389/fnmol.2017.00063PMC PMC5344993
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Abstract

Extracellular neuritic plaques, composed of aggregated amyloid-β (Aβ) peptides, are one of the major histopathological hallmarks of Alzheimer’s disease (AD), a progressive, irreversible neurodegenerative disorder and the most common cause of dementia in the elderly. One of the most prominent risk factor for sporadic AD, carrying one or two aberrant copies of the apolipoprotein E (ApoE) ɛ4 alleles, closely links AD to lipids. Further, several lipid classes and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipid changes in the brain seem not only to be a consequence of the disease but also modulate Aβ generation. In line with these observations protective lipids being able to decrease Aβ generation and also potential negative lipids in respect to AD were identified. Mechanistically, Aβ peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. The α-secretase appears to compete with β-secretase for the initial cleavage of APP, preventing Aβ production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipids on Aβ generation. Beside the pathological impact of Aβ, accumulating evidence suggests that Aβ and the APP intracellular domain (AICD) play an important role in regulating lipid homeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesis of different lipid classes. This review summarizes the current literature addressing the complex bidirectional link between lipids and AD and APP processing including lipid alterations found in AD post mortem brains, lipids that alter APP processing and the physiological functions of Aβ and AICD in the regulation of several lipid metabolism pathways.

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Figure 1 Overview of the two alternative amyloid precursor protein (APP) processing pathways, which are highly influenced by lipid homeostasis. Amyloidogenic pathway: APP is first cleaved by the β-secretase β-site APP cleaving enzyme 1 (BACE1) resulting in the release of sAPPβ and the generation of C99, which is further processed by the γ-secretase complex to amyloid-β (Aβ)-peptides and the APP intracellular domain (AICD). The neurotoxic Aβ-peptides can be cleared by different mechanisms including enzymatic degradation. The intracellular AICD-domain is known to translocate into the nucleus and to regulate the transcription of several target genes. Non-amyloidogenic pathway: APP is cleaved by the α-secretases belonging to the ADAM protein family within the Aβ-domain. This results in the release of sAPPα into the extracellular space and the formation of C83. C83 is further processed by the γ-secretase complex resulting in the release of the non-toxic peptide p3 into the extracellular space and of AICD into the cytosol. In contrast to the AICD generated by amyloidogenic APP processing the AICD derived from α-/γ-secretase-dependent APP processing is rapidly degraded in the cytosol and transcriptionally inactive.
Figure 1 Overview of the two alternative amyloid precursor protein (APP) processing pathways, which are highly influenced by lipid homeostasis. Amyloidogenic pathway: APP is first cleaved by the β-secretase β-site APP cleaving enzyme 1 (BACE1) resulting in the release of sAPPβ and the generation of C99, which is further processed by the γ-secretase complex to amyloid-β (Aβ)-peptides and the APP intracellular domain (AICD). The neurotoxic Aβ-peptides can be cleared by different mechanisms including enzymatic degradation. The intracellular AICD-domain is known to translocate into the nucleus and to regulate the transcription of several target genes. Non-amyloidogenic pathway: APP is cleaved by the α-secretases belonging to the ADAM protein family within the Aβ-domain. This results in the release of sAPPα into the extracellular space and the formation of C83. C83 is further processed by the γ-secretase complex resulting in the release of the non-toxic peptide p3 into the extracellular space and of AICD into the cytosol. In contrast to the AICD generated by amyloidogenic APP processing the AICD derived from α-/γ-secretase-dependent APP processing is rapidly degraded in the cytosol and transcriptionally inactive.CC BY · PubMed Central
Figure 2 Summary of the bidirectional link between proteolytic processing of the APP and lipid homeostasis. In brain tissue affected by Alzheimer’s disease (AD) the levels of several lipid classes and fatty acids are altered (indicated by ↓ = decreased, ↑ = increased). Lipids and fatty acids have a strong impact on the cerebral Aβ-levels and there is also a regulation of lipid homeostasis by the APP-processing products Aβ and AICD (delineated by + = increasing effect, − = decreasing effect) indicating the existence of complex regulatory cycles between lipid homeostasis and proteolytic APP processing (green arrows = beneficial effects, red arrows = negative effects, gray arrows = neutral/unknown effects). AGPS, alkyl-dihydroxyacetonephosphate-synthase; DHA, docosahexaenoic acid; GCS, glycosylceramide synthase; GD3S, GD3-synthase; HMGCR, hydroxymethylglutaryl-CoA reductase; PLA2, phospholipase A2; S1P, sphingosine 1-phosphate; SMases, sphingomyelinases; SPT, the serine palmitoyl-CoA transferase.
Figure 2 Summary of the bidirectional link between proteolytic processing of the APP and lipid homeostasis. In brain tissue affected by Alzheimer’s disease (AD) the levels of several lipid classes and fatty acids are altered (indicated by ↓ = decreased, ↑ = increased). Lipids and fatty acids have a strong impact on the cerebral Aβ-levels and there is also a regulation of lipid homeostasis by the APP-processing products Aβ and AICD (delineated by + = increasing effect, − = decreasing effect) indicating the existence of complex regulatory cycles between lipid homeostasis and proteolytic APP processing (green arrows = beneficial effects, red arrows = negative effects, gray arrows = neutral/unknown effects). AGPS, alkyl-dihydroxyacetonephosphate-synthase; DHA, docosahexaenoic acid; GCS, glycosylceramide synthase; GD3S, GD3-synthase; HMGCR, hydroxymethylglutaryl-CoA reductase; PLA2, phospholipase A2; S1P, sphingosine 1-phosphate; SMases, sphingomyelinases; SPT, the serine palmitoyl-CoA transferase.CC BY · PubMed Central

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  1. World Alzheimer Report, 2015, Alzheimer’s Disease International

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Metadata

Authors
Grimm, M. O. W., Mett, J., Grimm, H. S., & Hartmann, T.
Affiliations
Saarland University (DE)
Corresponding author
Grimm, Marcus O. W.
ORCID
Venue
Frontiers in Molecular Neuroscience
Publisher
Frontiers Media SA
Published
2017-03-10
Volume
10
Pages
63-63
ISSN
1662-5099 (ISSN-L)
DOI
10.3389/fnmol.2017.00063
PMC
PMC5344993
OpenAlex
W2594288299
Cited by
104
References
265
Citations by year
2026: 6 · 2025: 10 · 2024: 5 · 2023: 17 · 2022: 7 · 2021: 19 · 2020: 13 · 2019: 11 · 2018: 12 · 2017: 4
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
EU Joint Programme – Neurodegenerative Disease Research
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid-beta, amyloid precursor protein, APOE ε4, lipid metabolism, beta-secretase, gamma-secretase, alpha-secretase, APP intracellular domain, lipid homeostasis, fatty acids, neuritic plaques, lipid dysregulation

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