Mutational analysis in familial Alzheimer’s disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile

Lin, Yao‐Ping; Cheng, Chih‐Ya; Liao, Yi‐Chu; Hong, Chien Tai; Fuh, Jong‐Ling

doi:10.1038/s41598-020-76794-9

Cited by 9 publications

(4 citation statements)

References 48 publications

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“…Research reported 9 cases with the PSEN1 G206D mutation, most of whom had a family history, including 5 patients whose pedigrees were rst reported in France in 2005, with an onset age ranging from 32 to 34 years, though detailed clinical information was lacking 4 . The clinical characteristics of other patients were summarized in Table 1 [5][6][7] . This patient we reported was characterized by initial cognitive impairment, early-onset seizure, no neuropsychiatric symptoms, slow progression, and good response to the medications for cognitive improvement and seizure.…”

Section: Discussionmentioning

confidence: 99%

Nonfamilial early-onset Alzheimer's disease associated with de novo PSEN1 mutation: A case report and review of the literature

Qi,

Zheng,

et al. 2024

Preprint

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Background Alzheimer's disease (AD) is the most common cognitive disorder, and onset before the age of 65 is defined as early-onset AD (EOAD), accompanied with nonfamilial presenilin 1 (PSEN1) mutation rarely reported. KCNQ2 is a transmembrane potassium channel gene is responsible for epilepsy, the relationship between KCNQ2 mutation and AD with epilepsy is not clear, and there are no reports on the phenotype of KCNQ2 mutation in EOAD. Case presentation we reported a 38-year-old male patient who lacks a family history of AD, presenting with cognitive impairment and seizure at the early stage of disease. After excluding other neurological disorders via a series of comprehensive examinations, including neuropsychological assessment, genetic test, cerebrospinal fluid measurements, 18F-fluorodeoxy glucose-positron emission tomography (PET), 11C-Pittsburgh compound B-PET and 18F-flortaucipir-PET/CT, etc., the patient was finally diagnosed as EOAD with a de novo c.617G > A, (p.Gly206Asp) PSEN1 mutation combined with c.1490G > A (p.Arg497His) potassium voltage-gated channel subfamily Q member 2 (KCNQ2) mutation by AD biomarkers measurements and whole exome sequencing, with different clinical characteristics from previously reported PSEN1 G206D mutation. Conclusions Our case emphasizes the need to consider neurodegenerative diseases in young patients manifesting early cognitive impairment and seizure but lacking a family history of AD, and biomarkers and genes of AD should be tested to make diagnosis. Medication by targeting the brain-gut axis but without the risk of causing seizure is optimal for attenuating cognitive symptoms. KCNQ2 mutation and its role in the development and clinical phenotype of AD needs further exploration.

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Section: Discussionmentioning

confidence: 99%

Nonfamilial early-onset Alzheimer's disease associated with de novo PSEN1 mutation: A case report and review of the literature

Qi,

Zheng,

et al. 2024

Preprint

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“…We used familial AD (PSEN1 M146I) iPSC-derived NSCs and confirmed that trametinib could induce neuronal differentiation. The PSEN1 M146I mutation is a widespread mutation in AD patients with PSEN1 mutations 56 . Therefore, it is reasonable to expect that trametinib can induce neurogenesis in an AD patient’s brain.…”

Section: Discussionmentioning

confidence: 99%

Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer’s disease

Kim,

Lee

et al. 2023

Exp Mol Med

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Enhancing adult neurogenesis in the brain has been suggested as a potential therapeutic strategy for AD. We developed a screening platform, ATRIVIEW®, for molecules that activate neuronal differentiation of adult mouse NSCs. The most potent hit from an FDA-approved drug library was SNR1611 (trametinib), a selective MEK1/2 inhibitor. We found that trametinib increases the levels of P15INK4b and Neurog2, suggesting a mechanism by which MEK1/2 inhibition induces neuronal differentiation. Oral administration of trametinib increased adult neurogenesis in the dentate gyrus and subventricular zone of the 5XFAD AD mouse model. Surprisingly, we also found that trametinib enhanced adult neurogenesis in the cortex. Consequently, trametinib rescued AD pathologies such as neuronal loss and cognitive impairment in 5XFAD mice. Finally, trametinib induced neurogenic differentiation of NSCs derived from AD patient iPSCs, which suggests its potential therapeutic application. Altogether, we suggest that restoration of endogenous adult neurogenesis by trametinib may be a promising therapeutic approach to AD.

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“…ADAD is caused by mutations or duplications of the amyloid precursor protein ( APP ), mutations in presenilin 1 ( PSEN1 ), or mutations in presenilin 2 ( PSEN2 ), an autosomal dominant inheritance within family members for more than two generations, and an onset earlier than 65 years old [ 4 , 5 ]. More than 400 mutations have been reported on these three genes, but PSEN1 harbors the most mutations, which are also associated with the youngest age at onset with affected individuals typically being 30–50 years old [ 4 , 6 – 8 ]. In fact, PSEN1 mutations have also been reported in late-onset AD [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Circular RNA detection identifies circPSEN1 alterations in brain specific to autosomal dominant Alzheimer's disease

Chen

Eteleeb

Wang

et al. 2022

acta neuropathol commun

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Background Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (< 65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD. Methods We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software. Results Our results show significant differences in gene counts of circPSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD = 21, AD = 253, Controls = 23—ADADvsCO: log2FC = 0.794, p = 1.63 × 10–04, ADADvsAD: log2FC = 0.602, p = 8.22 × 10–04). The high gene counts are contributed by two circPSEN1 species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circPSEN1 is involved in several pathways such as axon guidance (p = 3.39 × 10–07), hippo signaling pathway (p = 7.38 × 10–07), lysine degradation (p = 2.48 × 10–05) or Wnt signaling pathway (p = 5.58 × 10–04) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70. Conclusions Our findings show the differential expression of circPSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.

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Mutational analysis in familial Alzheimer’s disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile

Cited by 9 publications

References 48 publications

Nonfamilial early-onset Alzheimer's disease associated with de novo PSEN1 mutation: A case report and review of the literature

Nonfamilial early-onset Alzheimer's disease associated with de novo PSEN1 mutation: A case report and review of the literature

Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer’s disease

Circular RNA detection identifies circPSEN1 alterations in brain specific to autosomal dominant Alzheimer's disease

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