Knockdown of Amyloid Precursor Protein: Biological Consequences and Clinical Opportunities

Gabriele, Rebecca M. C.; Abel, Emily K.; Fox, Nick C.; Wray, Selina; Arber, Charles

doi:10.3389/fnins.2022.835645

Cited by 15 publications

(11 citation statements)

References 129 publications

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“…APLP1 and APLP2 are close homologues of APP with apparent overlapping functions . Although not everything is understood to great detail, APLP2 like APP is involved in neurite growth .…”

Section: App Homologue Aplp2mentioning

confidence: 99%

Substrate Selection Criteria in Regulated Intramembrane Proteolysis

Moser,

Guschtschin-Schmidt,

Silber

et al. 2024

ACS Chem. Neurosci.

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Alzheimer's disease is the most common form of dementia encountered in an aging population. Characteristic amyloid deposits of Aβ peptides in the brain are generated through cleavage of amyloid precursor protein (APP) by γ-secretase, an intramembrane protease. Cryo-EM structures of substrate γ-secretase complexes revealed details of the process, but how substrates are recognized and enter the catalytic site is still largely ignored. γ-Secretase cleaves a diverse range of substrate sequences without a common consensus sequence, but strikingly, single point mutations within the transmembrane domain (TMD) of specific substrates may greatly affect cleavage efficiencies. Previously, conformational flexibility was hypothesized to be the main criterion for substrate selection. Here we review the 3D structure and dynamics of several γ-secretase substrate TMDs and compare them with mutants shown to affect the cleavage efficiency. In addition, we present structural and dynamic data on ITGB1, a known nonsubstrate of γsecretase. A comparison of biophysical details between these TMDs and changes generated by introducing crucial mutations allowed us to unravel common principles that differ between substrates and nonsubstrates. We identified three motifs in the investigated substrates: a highly flexible transmembrane domain, a destabilization of the cleavage region, and a basic signature at the end of the transmembrane helix. None of these appears to be exclusive. While conformational flexibility on its own may increase cleavage efficiency in well-known substrates like APP or Notch1, our data suggest that the three motifs seem to be rather variably combined to determine whether a transmembrane helix is efficiently recognized as a γ-secretase substrate.

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“…APLP1 and APLP2 are close homologues of APP with apparent overlapping functions . Although not everything is understood to great detail, APLP2 like APP is involved in neurite growth .…”

Section: App Homologue Aplp2mentioning

confidence: 99%

Substrate Selection Criteria in Regulated Intramembrane Proteolysis

Moser,

Guschtschin-Schmidt,

Silber

et al. 2024

ACS Chem. Neurosci.

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“…PAX6, in turn, directly regulates the transcription of GSK-3β, which further catalyzes amyloid-β-mediated tau phosphorylation [509,510]. Since CTCF decreases with age, it does not seem to directly upregulate APP in AD [511,512]. However, the decline in CTCF might indirectly interfere with APP expression.…”

Section: App and Taumentioning

confidence: 99%

Role of primary aging hallmarks in Alzheimer´s disease

Zhao¹,

Huai²

2023

Theranostics

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Alzheimer's disease (AD) is the most common neurodegenerative disease, which severely threatens the health of the elderly and causes significant economic and social burdens. The causes of AD are complex and include heritable but mostly aging-related factors. The primary aging hallmarks include genomic instability, telomere wear, epigenetic changes, and loss of protein stability, which play a dominant role in the aging process. Although AD is closely associated with the aging process, the underlying mechanisms involved in AD pathogenesis have not been well characterized. This review summarizes the available literature about primary aging hallmarks and their roles in AD pathogenesis. By analyzing published literature, we attempted to uncover the possible mechanisms of aberrant epigenetic markers with related enzymes, transcription factors, and loss of proteostasis in AD. In particular, the importance of oxidative stress-induced DNA methylation and DNA methylation-directed histone modifications and proteostasis are highlighted. A molecular network of gene regulatory elements that undergoes a dynamic change with age may underlie age-dependent AD pathogenesis, and can be used as a new drug target to treat AD.

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“…For example, Aβ, tau, alpha-synuclein, and TDP-43 are known to localize on the mitochondrial membrane and prevent neurons from functioning normally by causing mitochondrial damage, disrupting the election transport chain, increasing the production of reactive oxygen species and inducing persistent neuroinflammation and glutamate excitotoxicity [131][132][133][134][135][136]. Interestingly, the knockdown of these proteins does not cure or ameliorate neurodegeneration but rather results in severe motor (i.e., motor neuron degeneration), cognitive (i.e., spatial and long-term memory), and behavioral abnormalities (i.e., anxiety-like behavior) [137][138][139][140]. These deficits reflect the essential role these proteins play in regulating the morphology and physiology of neurons (i.e., neural growth and repair, cytoskeleton scaffolding, regulation of gene expression, and neurotransmitter release) [141][142][143][144].…”

Section: Neurodegenerationmentioning

confidence: 99%

Linking Puberty and the Gut Microbiome to the Pathogenesis of Neurodegenerative Disorders

Esposito

Ismail

2022

Microorganisms

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Puberty is a critical period of development marked by the maturation of the central nervous system, immune system, and hypothalamic–pituitary–adrenal axis. Due to the maturation of these fundamental systems, this is a period of development that is particularly sensitive to stressors, increasing susceptibility to neurodevelopmental and neurodegenerative disorders later in life. The gut microbiome plays a critical role in the regulation of stress and immune responses, and gut dysbiosis has been implicated in the development of neurodevelopmental and neurodegenerative disorders. The purpose of this review is to summarize the current knowledge about puberty, neurodegeneration, and the gut microbiome. We also examine the consequences of pubertal exposure to stress and gut dysbiosis on the development of neurodevelopmental and neurodegenerative disorders. Understanding how alterations to the gut microbiome, particularly during critical periods of development (i.e., puberty), influence the pathogenesis of these disorders may allow for the development of therapeutic strategies to prevent them.

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Knockdown of Amyloid Precursor Protein: Biological Consequences and Clinical Opportunities

Cited by 15 publications

References 129 publications

Substrate Selection Criteria in Regulated Intramembrane Proteolysis

Substrate Selection Criteria in Regulated Intramembrane Proteolysis

Role of primary aging hallmarks in Alzheimer´s disease

Linking Puberty and the Gut Microbiome to the Pathogenesis of Neurodegenerative Disorders

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