Clinical characterization of an APP mutation (V717I) in five Han Chinese families with early-onset Alzheimer's disease

Zhang, Guili; Xie, Yunyan; Wang, Wei; Feng, Xueyan; Jia, Jianping

doi:10.1016/j.jns.2016.10.039

Cited by 20 publications

(18 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The FAD/early-onset AD-linked V717I "London" AβPP mutation [2,3] increases AβPP cleavage into Aβ and shifts the proportions of the cleavage products in favor of the highly neurotoxic Aβ 42 [4]. Little is known on other aspects of the influence of the mutation on the (still elusive) functions of AβPP in neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Synergy has also been reported between Aβ 42 toxicity and ApoE allele [6]. Moreover, the effect of "London" mutation leads to different sets of symptoms in patients of various ethnic origins and has been suggested to be modified by other genetic or environmental factors [2]. Mouse model expressing the V717I AβPP under control of the neuron-specific mouse thy-1 promoter (AβPP expression strongest in large pyramidal neurons of hippocampus, cerebral cortex, and amygdala) has been created and characterized [7].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

et al. 2018

View full text Add to dashboard Cite

Sphingolipid signaling disturbances correlate with Alzheimer's disease (AD) progression. We examined the influence of FTY720/fingolimod, a sphingosine analog and sphingosine-1-phosphate (S1P) receptor modulator, on the expression of sphingolipid metabolism and signaling genes in a mouse transgenic AD model. Our results demonstrated that AβPP (V717I) transgene led with age to reduced mRNA expression of S1P receptors (S1PRs), sphingosine kinase SPHK2, ceramide kinase CERK, and the anti-apoptotic Bcl2 in the cerebral cortex and hippocampus, suggesting a pro-apoptotic shift in 12-month old mice. These changes largely emulated alterations we observed in the human sporadic AD hippocampus: reduced SPHK1, SPHK2, CERK, S1PR1, and BCL2. We observed that the responses to FTY720 treatment were modified by age and notably differed between control (APP − ) and AD transgenic (APP + ) animals. AβPP (V717I)-expressing 12-month-old animals reacted to fingolimod with wide changes in the gene expression program in cortex and hippocampus, including increased pro-survival SPHKs and CERK. Moreover, BCL2 was elevated by FTY720 in the cortex at all ages (3, 6, 12 months) while in hippocampus this increase was observed at 12 months only. In APP − mice, fingolimod did not induce any significant mRNA changes at 12 months. Our results indicate significant effect of FTY720 on the age-dependent transcription of genes involved in sphingolipid metabolism and pro-survival signaling, suggesting its neuroprotective role in AD animal model.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Extracellular senile plaques of amyloid β (Aβ) are a hallmark and a crucial element of AD neuropathology [2]. The V717I "London" mutation of Aβ precursor protein (AβPP) has been reported in familial (FAD)/early-onset AD [3]. The mutation increases Aβ production and shifts the AβPP metabolism in favor of the highly neurotoxic Aβ 42 isoform [4].…”

Section: Introductionmentioning

confidence: 99%

Fingolimod Affects Transcription of Genes Encoding Enzymes of Ceramide Metabolism in Animal Model of Alzheimer’s Disease

et al. 2020

View full text Add to dashboard Cite

The imbalance in sphingolipid signaling may be critically linked to the upstream events in the neurodegenerative cascade of Alzheimer's disease (AD). We analyzed the influence of mutant (V717I) amyloid β precursor protein (AβPP) transgene on sphingolipid metabolism enzymes in mouse hippocampus. At 3 months of age AβPP/Aβ presence upregulated enzymes of ceramide turnover on the salvage pathway: ceramide synthases (CERS2, CERS4, CERS6) and also ceramidase ACER3. At 6 months, only CERS6 was elevated, and no ceramide synthase was increased at 12 months. However, sphingomyelin synthases, which utilize ceramide on the sphingomyelinase pathway, were reduced (SGMS1 at 12 and SGMS2 at 6 months). mRNAs for sphingomyelin synthases SGMS1 and SGMS2 were also significantly downregulated in human AD hippocampus and neocortex when compared with age-matched controls. Our findings suggest early-phase deregulation of sphingolipid homeostasis in favor of ceramide signaling. Fingolimod (FTY720), a modulator of sphingosine-1-phosphate receptors countered the AβPP-dependent upregulation of hippocampal ceramide synthase CERS2 at 3 months. Moreover, at 12 months, FTY720 increased enzymes of ceramide-sphingosine turnover: CERS4, ASAH1, and ACER3. We also observed influence of fingolimod on the expression of the sphingomyelinase pathway enzymes. FTY720 counteracted the AβPP-linked reduction of sphingomyelin synthases SGMS1/2 (at 12 and 6 months, respectively) and led to elevation of sphingomyelinase SMPD2 (at 6 and 12 months). Therefore, our results demonstrate potentially beneficial, age-specific effects of fingolimod on transcription of sphingolipid metabolism enzymes in an animal model of AD.

show abstract

“…ADAD associated mutations in APP mainly cluster around these secretase cleavage sites, while codon 717 is a mutational hotspot at the γ-secretase cleavage site [27]. To date, four different pathogenic amino acid changes for APP on codon 717 have been described: Valine to Phenylalanine (V717F, Indiana [37]), Valine to Glycine (V717G [10]), Valine to Isoleucine (V717I, London [18,63]) and Valine to Leucine (V717L [38]). All of these mutations shift the ratio of Aβ 1-42 /Aβ 1-40 towards increased production of Aβ 1-42 [27], which is more aggregation prone and can drive pathological protein accumulation.…”

Section: Introductionmentioning

confidence: 99%

Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier – phenotypic variability in autosomal dominant Alzheimer’s disease

Lloyd

Trejo‐Lopez

Xia

et al. 2020

acta neuropathol commun

View full text Add to dashboard Cite

The discovery of mutations associated with familial forms of Alzheimer's disease (AD), has brought imperative insights into basic mechanisms of disease pathogenesis and progression and has allowed researchers to create animal models that assist in the elucidation of the molecular pathways and development of therapeutic interventions. Position 717 in the amyloid precursor protein (APP) is a hotspot for mutations associated with autosomal dominant AD (ADAD) and the valine to isoleucine amino acid substitution (V717I) at this position was among the first ADAD mutations identified, spearheading the formulation of the amyloid cascade hypothesis of AD pathogenesis. While this mutation is well described in multiple kindreds and has served as the basis for the generation of widely used animal models of disease, neuropathologic data on patients carrying this mutation are scarce. Here we present the detailed clinical and neuropathologic characterization of an APP V717I carrier, which reveals important novel insights into the phenotypic variability of ADAD cases. While age at onset, clinical presentation and widespread parenchymal beta-amyloid (Aβ) deposition are in line with previous reports, our case also shows widespread and severe cerebral amyloid angiopathy (CAA). This patient also presented with TDP-43 pathology in the hippocampus and amygdala, consistent with limbic predominant age-related TDP-43 proteinopathy (LATE). The APOE ε2/ε3 genotype may have been a major driver of the prominent vascular pathology seen in our case. These findings highlight the importance of neuropathologic examinations of genetically determined AD cases and demonstrate striking phenotypic variability in ADAD cases.

show abstract

Clinical characterization of an APP mutation (V717I) in five Han Chinese families with early-onset Alzheimer's disease

Cited by 20 publications

References 38 publications

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

Fingolimod Affects Transcription of Genes Encoding Enzymes of Ceramide Metabolism in Animal Model of Alzheimer’s Disease

Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier – phenotypic variability in autosomal dominant Alzheimer’s disease

Contact Info

Product

Resources

About