Regressive Autism Spectrum Disorder: High Levels of Total Secreted Amyloid Precursor Protein and Secreted Amyloid Precursor Protein-α in Plasma

Li, Xiaoli; Zhou, Ping; Li, Qiu; Peng, Bin; Cun, Yupeng; Dai, Ying; Wei, Hua; Liu, Xiao; Yu, Yang; Jiang, Zhiyang; Fan, Qiong-Li; Zhang, Yuping; Yang, Ting; Chen, Jie; Qian, Cheng; Li, Tingyu; Chen, Li

doi:10.3389/fpsyt.2022.809543

Cited by 5 publications

(6 citation statements)

References 68 publications

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“…29,30 Derangements in amyloid processing may also be involved in ASD. [31][32][33][34] Interestingly, VPA has been found to inhibit g-secretase cleavage of amyloid precursor protein, reducing brain amyloid load and VPA hypocholesterolemic effects could be a mechanism contributing to its favorable impact on ASD via amyloid reduction. 35 This requires further exploration as most studies of this relationship have focused on cognitive impairment in older population and not on developmental effects on amyloid.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol deficiency as a mechanism for autism: A valproic acid model

Peltier,

Behbodikhah,

Renna

et al. 2023

Journal of Investigative Medicine

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Dysregulated cholesterol metabolism represents an increasingly recognized feature of Autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Further, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36 and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

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Section: Discussionmentioning

confidence: 99%

Cholesterol deficiency as a mechanism for autism: A valproic acid model

Peltier,

Behbodikhah,

Renna

et al. 2023

Journal of Investigative Medicine

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“…In contrast, increased Aβ levels have been observed in plasma and post-mortem brain samples of adult FXS individuals and in adult Fmr1 KO mice [18,20,37,76], supporting the development-dependent dysregulation of APP processing in FXS. Of note, high levels of sAPPα have also been reported in the plasma of juvenile idiopathic autistic patients [37][38][39][77][78][79][80][81], in ASD individuals with severe clinical manifestations [78][79][80] and subjects with Angelman syndrome [82], suggesting that sAPPα may play a critical role in the pathogenesis of different neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, a clinical manifestation that tends to resolve over time is the presence of seizures [6,102]. Interestingly, seizures have also been reported in individuals with ASD [103,104] and with Angelman syndrome [105,106], which share with FXS the excessive sAPPα production [78][79][80]82].…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals

Cencelli

Pacini

Luca

et al. 2023

Cells

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Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window.

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“…Li X et al [ 49 ] found higher plasma levels of total secreted amyloid precursor protein (sAPPtotal) and of secreted amyloid precursor protein-α (sAPPα) in children with RO-ASD compared to children with non-regressive ASD and typically developing controls. APP is a glycoprotein secreted by glial cells and neurons that promotes neuronal proliferation and migration, cell adhesion, and synapse formation.…”

Section: Discussionmentioning

confidence: 99%

The Role of SNAP-25 in Autism Spectrum Disorders Onset Patterns

Bolognesi,

Guerini,

Carta

et al. 2023

IJMS

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Autism spectrum disorders (ASD) can present with different onset and timing of symptom development; children may manifest symptoms early in their first year of life, i.e., early onset (EO-ASD), or may lose already achieved skills during their second year of life, thus showing a regressive-type onset (RO-ASD). It is still controversial whether regression represents a neurobiological subtype of ASD, resulting from distinct genetic and environmental causes. We focused this study on the 25 kD synaptosomal-associated protein (SNAP-25) gene involved in both post-synaptic formation and adhesion and considered a key player in the pathogenesis of ASD. To this end, four single nucleotide polymorphisms (SNPs) of the SNAP-25 gene, rs363050, rs363039, rs363043, and rs1051312, already known to be involved in neurodevelopmental and psychiatric disorders, were analyzed in a cohort of 69 children with EO-ASD and 58 children with RO-ASD. Both the rs363039 G allele and GG genotype were significantly more frequently carried by patients with EO-ASD than those with RO-ASD and healthy controls (HC). On the contrary, the rs1051312 T allele and TT genotype were more frequent in individuals with RO-ASD than those with EO-ASD and HC. Thus, two different SNAP-25 alleles/genotypes seem to discriminate between EO-ASD and RO-ASD. Notably, rs1051312 is located in the 3′ untranslated region (UTR) of the gene and is the target of microRNA (miRNA) regulation, suggesting a possible epigenetic role in the onset of regressive autism. These SNPs, by discriminating two different onset patterns, may represent diagnostic biomarkers of ASD and may provide insight into the different biological mechanisms towards the development of better tailored therapeutic and rehabilitative approaches.

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Regressive Autism Spectrum Disorder: High Levels of Total Secreted Amyloid Precursor Protein and Secreted Amyloid Precursor Protein-α in Plasma

Cited by 5 publications

References 68 publications

Cholesterol deficiency as a mechanism for autism: A valproic acid model

Cholesterol deficiency as a mechanism for autism: A valproic acid model

Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals

The Role of SNAP-25 in Autism Spectrum Disorders Onset Patterns

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