Author
Dun-Shen Yang
Bio: Dun-Shen Yang is an academic researcher. The author has contributed to research in topics: BACE1-AS & Presenilin. The author has an hindex of 1, co-authored 1 publications receiving 928 citations.
Papers
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TL;DR: High level production of the pathogenic Aβ42 form of Aβ peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age.
986 citations
Cited by
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University College London1, National Institutes of Health2, Mayo Clinic3, University of Toronto4, Brigham Young University5, Cardiff University6, Lille University of Science and Technology7, Washington University in St. Louis8, University of Nottingham9, King's College London10, University of Cambridge11
TL;DR: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease.
Abstract: BACKGROUND:
Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.
METHODS:
We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.
RESULTS:
We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.
CONCLUSIONS:
Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).
2,333 citations
TL;DR: It is shown that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR), which uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity.
1,611 citations
TL;DR: It is reported that a long noncoding RNA is directly implicated in the increased abundance of Aβ 1–42 in Alzheimer's disease.
Abstract: BACE is an enzyme necessary for the generation of neurotoxic amyloid-β in Alzheimer's disease. Claes Wahlestedt and his colleagues identify a noncoding RNA that is upregulated in the brains of individuals with Alzheimer's disase. This noncoding RNA increases expression of BACE, driving amyloid-β generation and possibly disease progression.
1,264 citations
TL;DR: Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise into a variety of neurological disorders.
Abstract: Sensory experience and the resulting synaptic activity within the brain are critical for the proper development of neural circuits. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the synaptic connectivity within the neural circuit. One way in which calcium influx leads to the remodeling of synapses made by neurons is through the activation of new gene transcription. Recent studies have identified many of the signaling pathways that link neuronal activity to transcription, revealing both the transcription factors that mediate this process and the neuronal activity-regulated genes. These studies indicate that neuronal activity regulates a complex program of gene expression involved in many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise to a variety of neurological disorders.
781 citations
TL;DR: Evidence is reviewed for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease, with particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity.
762 citations