EphA4 regulates Aβ production via BACE1 expression in neurons

Tamura, Kensuke; Chiu, Yung-Wen; Shiohara, Azusa; Hori, Yukiko; Tomita, Taisuke

doi:10.1096/fj.202001510r

Cited by 12 publications

(8 citation statements)

References 56 publications

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“…Apart from neurotransmission-associated molecular functions, molecular functional pathway analysis revealed this list to be significantly enriched for genes defined as “amyloid-beta binding” (fold enrichment = 7.79, p (FDR) = 0.01) ( Fig. 3A ), including SORL1 , an endocytic receptor that directs the amyloid precursor protein away from the amyloidogenic pathway (43–45) and EPHA4 , a receptor tyrosine kinase involved in amyloid regulation (46). Since α5-containing nicotinic receptors are highly permeable to calcium ions (21,22), we note that chandelier neurons are also significantly enriched for genes with a “calcium ion binding” molecular function (fold enrichment = 3.77, p (FDR) = 4.12*10 −6 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

Rybnicek

Chen

Milic

et al. 2022

Preprint

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Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to cognitive impairment in Alzheimer's Disease (AD). While preclinical work suggests a possible protective and cognitive-enhancing role for the auxiliary nicotinic α5 subunit, mRNA expression of the CHRNA5 gene has not been closely examined in the context of human aging and dementia. Here, we investigate the impact of two common SNPs predicted to have different effects on the nicotinic α5 subunit: the function-compromising rs16969968 and the expression-altering rs1979905. We analyzed data from human prefrontal cortex (922 subjects with matched genotypic and post-mortem RNA sequencing, including 22 subjects with single-nucleus data) of elderly participants in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We tested the impact of SNP haplotypes on prefrontal expression of CHRNA5 as well as that of SNPs in its receptor partners: CHRNA4 and CHRNB2. In the context of cognition and neuropathology, we observed a significant negative association between the high CHRNA5-expressing rs1979905A2 genotype and β-amyloid load in the prefrontal cortex. Our analyses revealed that the greatest abundance of CHRNA5 expression was in chandelier neurons, a sparse but disproportionately-powerful set of interneurons, in addition to layer 5 and 6 pyramidal neurons. In subjects with functionally-unaltered CHRNA5, the proportion of chandelier cells in the prefrontal cortex shows resilience to β-amyloid load, but this resilience is diminished in subjects homozygous for the minor allele of the CHRNA5 missense SNP rs16969968. Taken together, these findings urge further investigation into the role of CHRNA5 and chandelier cells in AD neuroprotection.

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Section: Resultsmentioning

confidence: 99%

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

Rybnicek

Chen

Milic

et al. 2022

Preprint

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“…It further added that the expression level of EphA‐4 decreases in the transgenic murine model of AD before the onset of cognitive impairment (Simón et al, 2009). Recently, Tamura et al (2020) observed that the expression of EphA‐4 declines with AD that correlated negatively with the level of the BACE1 gene.…”

Section: The Pathophysiology Of Ad Due To Ephrine Receptorsmentioning

confidence: 99%

“…Surprisingly, several reports exist that support the protective role of EphA‐4 in AD pathogenesis. For example, pharmacological and genetic ablation of EphA‐4 leads to an increase in the expression of BACE1, an enzyme responsible for producing Aβ (Tamura et al, 2020). EphA‐4 signalling in a platelet‐derived growth factor receptor β (PDGFRβ) dependent manner promotes the proliferation of neural progenitor cells (NPCs) and alleviates cognitive impairment in a murine transgenic AD model (Chen et al, 2020).…”

Section: The Pathophysiology Of Ad Due To Ephrine Receptorsmentioning

confidence: 99%

“…Notably, AICD have emerged as critical player in the pathogenesis alongside Aβ. Cdk5 (cyclin dependent kinase 5); AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid); Pyk2 (Proline-rich tyrosine kinase 2); FAK (focal adhesion kinase); Cas (Crk-associated substrate), and AICD (APP intracellular domain) enzyme responsible for producing Aβ (Tamura et al, 2020). EphA-4 signalling in a platelet-derived growth factor receptor β (PDGFRβ) dependent manner promotes the proliferation of neural progenitor cells (NPCs) and alleviates cognitive impairment in a murine transgenic AD model (Chen et al, 2020).…”

Section: The Pathophysiology Of Ad Due To Ephrine Receptorsmentioning

confidence: 99%

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Mechanistic and therapeutic implications of EphA‐4 receptor tyrosine kinase in the pathogenesis of Alzheimer's disease

Ganguly

Thomas

Ali

et al. 2022

Eur J of Neuroscience

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Erythropoietin-producing hepatoma (Eph) receptors belong to a family of tyrosine kinase receptors that plays a pivotal role in the development of the brain.Eph can be divided broadly into two groups, namely, EphA and EphB, comprising nine and five members, respectively. In recent years, the role of EphA-4 has become increasingly apparent in the onset of Alzheimer's disease (AD). Emerging evidence suggests that EphA-4 results in synaptic dysfunction, which in turn promotes the progression of AD. Moreover, pharmacological or genetic ablation of EphA-4 in the murine model of AD can alleviate the symptoms. The current review summarizes different pathways by which EphA-4 can influence pathogenesis. Since, majority of the studies had reported the protective effect of EphA-4 inhibition during AD, designing therapeutics based on decreasing its enzymatic activity might be necessary for introducing the novel interventions. Therefore, the review described peptide and nanobodies inhibitors of EphA-4 that exhibit the potential to modulate EphA-4 and could be used as lead molecules for the targeted therapy of AD.

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“…BIN1 and EphA4 are genetic risk factors for Alzheimer’s disease that mediate Aβ production via regulation of BACE1 transport and activity. 24 , 25 These findings motivated the development and testing of BACE1 inhibitors in drug trials, without reaching treatment endpoints and with indications of negative cognitive effects, other adverse effects, including regionally increased brain atrophy. 26–29 Side effects of BACE1 inhibitors are both on-target and off-target, and specificity for BACE1 inhibitors tested in clinical trials is also limited.…”

Section: Introductionmentioning

confidence: 99%

Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer’s disease patients

Kirsebom

Richter

Nordengen

et al. 2022

Brain Communications

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CSF BACE1 (β-site amyloid precursor protein cleaving enzyme 1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer’s disease. BACE1 is also a drug target. However, CSF levels may differ between early stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). It is unknown whether BACE1 and neurogranin levels are persistent traits or change with disease progression. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer’s disease cases (n=176) (including cases that progressed to dementia (n=10)) and controls (n=74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n=86) and late stage (A+/T+/N+, n=90) of the Alzheimer’s Disease continuum and controls with normal markers (A-/T-/N-, n=74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately two-year intervals up-to six years from baseline. Using Linear Mixed Models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n=12), from A+/T-/N- to A+/T or N+ (n=12), remained stable A+/T-/N- (n=26), remained stable A+/T+/N+ (n=28) compared to controls remaining stable A-/T-/N- (n=33). Lastly, associations between these markers and memory decline were assessed. Compared to A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (p<.0001). In contrast, BACE1 was lower in A+/T-/N- (p<.05) and higher in A+/T+/N+ (p<.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (p<.05) and A+/T+/N+ (p<.0001) groups as compared to A-/T-/N- healthy controls and more strongly associated with memory decline (b=-.29, p=.0006) than neurogranin (b=-.20, p=.002) and BACE1 (b=-.13, p=.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups, but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A+T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer’s Disease subgroups, putatively with different options for treatment.

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EphA4 regulates Aβ production via BACE1 expression in neurons

Cited by 12 publications

References 56 publications

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

Mechanistic and therapeutic implications of EphA‐4 receptor tyrosine kinase in the pathogenesis of Alzheimer's disease

Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer’s disease patients

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