SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

Kurkinen, Kaisa M.A.; Marttinen, Mikael; Turner, Laura; Natunen, Teemu; Mäkinen, Petra; Haapalinna, Fanni; Sarajärvi, Timo; Gabbouj, Sami; Kurki, Mitja; Paananen, Jussi; Koivisto, Anne M.; Rauramaa, Tuomas; Leinonen, Ville; Tanila, Heikki; Lucas, Fiona R.; Haapasalo, Annakaisa; Hiltunen, Mikko

doi:10.1242/jcs.185215

Cited by 18 publications

(23 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Septin‐8, which was found to reduce soluble APPβ and Aβ levels in neuronal cells by decreasing levels of BACE1 protein (Kurkinen et al . ), was increased in the HIP and decreased in the PFC and AMY of the OVX rats. Fbxo2, which facilitates the degradation of BACE1 (Atkin et al .…”

Section: Discussionmentioning

confidence: 77%

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

Fang

Zeng

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

Menopause, a risk factor for brain dysfunction in women, is characterized by neuropsychological symptoms including depression and dementia, which are closely related to alterations in different brain regions after menopause. However, little is known about the variability in pathophysiologic changes associated with menopause in the brain. Here, we observed that menopause in rats induced by bilateral ovariectomy (OVX) showed depressive and dementia-related behaviors along with neuronal loss in the prefrontal cortex (PFC), hippocampus (HIP), hypothalamus (HYP), and amygdala (AMY) by Nissl staining. Meanwhile, by immunohistochemical staining, increased microglia in the HIP and AMY and increased astrocytes in the PFC, HYP, and AMY were shown. Using quantitative proteomics, we identified 146 differentially expressed proteins in the brains of OVX rats, for example, 20 in the PFC, 41 in the HIP, 17 in the HYP, and 79 in the AMY, and performed further detection by western blotting. A link between neuronal loss and apoptosis was suggested, as evidenced by increases in adenylate kinase 2 (AK2), B-cell lymphoma 2 associated X (Bax), cleaved caspase 3, and phosphorylated p53 and decreases in Huntingtin-interacting protein K, hexokinase, and phosphorylated B-cell lymphoma 2 (Bcl-2), and apoptosis might be triggered by endoplasmic reticulum stress (probed by increased glucose-regulated protein 78 (GRP78), cleaved caspase 12, phosphorylated protein kinase R (PKR)-like endoplasmic reticulum kinase, inositol-requiring enzyme-1 and activating transcription factor 6), and mitochondrial dysfunction (probed by increased cytochrome c and cleaved caspase 3 and decreased sideroflexin-1 (SFXN1) and NADH dehydrogenase (ubiquinone) 1 α subcomplex 11 (NDUFA11)). Activation of autophagy was also indicated by increased autophagy-related 7, γ-aminobutyric acid (GABA) receptor-associated protein-like 2, and oxysterol-binding protein-related protein 1 and confirmed by increased microtubule-associated protein light chain 3 (LC3II/I), autophagy-related 5, and Beclin1 in the HIP and AMY. In the AMY, which is important in emotion, higher GABA transporter 3 and lower vesicular glutamate transporter 1 levels indicated an imbalance between excitatory and inhibitory neurotransmission, and the increased calretinin and decreased calbindin levels suggested an adjustment of GABAergic transmission after OVX. In addition, cytoskeletal abnormalities including tau hyperphosphorylation, dysregulated Ca² signals, and glutamic synaptic impairments were observed in the brains of OVX rats. Collectively, our study showed the changes in different brain regions related to depression and dementia during menopause.

show abstract

Section: Discussionmentioning

confidence: 77%

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

Fang

Zeng

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…The much lower levels of sAPPb and sAPPa in NDEs are significantly higher for patients with AD than in the AC subjects ( P = 0.0028 and P = 0.0008, respectively). The neural protein septin‐8 has been implicated in normal synaptic plasticity and in the regulation of amyloidogenic processing of APP through control of sorting and expression of BACE‐1 (18). ADE, but not NDE, levels of septin‐8 were significantly lower in patients with AD than in the AC subjects ( P < 0.0001), without a difference in ADE levels of patients with FTD than in controls.…”

Section: Resultsmentioning

confidence: 99%

“…Mechanisms of regulation of expression of BACE‐1 involve several transcriptional elements, such as type 1 specificity protein type 1 (Sp1) and NFAT3, as well as posttranscriptional events (15, 16). BACE‐1 stability and function also are influenced by other neural proteins, including ubiquilin‐1 and septin‐8 (17, 18). A greater understanding of the relative role of these astrocyte pathways in generation of Ab peptides in the brain has come from recent analyses of human induced pluripotent stem cell‐ derived neural cells (19).…”

mentioning

confidence: 99%

Cargo proteins of plasma astrocyte‐derived exosomes in Alzheimer's disease

et al. 2016

View full text Add to dashboard Cite

Efficient intercellular transfer of RNAs, proteins, and lipids as protected exosomal cargo has been demonstrated in the CNS, but distinct physiologic and pathologic roles have not been well defined for this pathway. The capacity to isolate immunochemically human plasma neuron-derived exosomes (NDEs), containing neuron-specific cargo, has permitted characterization of CNS-derived exosomes in living humans. Constituents of the amyloid β-peptide (Aβ)42-generating system now are examined in 2 distinct sets of human neural cells by quantification in astrocyte-derived exosomes (ADEs) and NDEs, enriched separately from plasmas of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD) and matched cognitively normal controls. ADE levels of β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), γ-secretase, soluble Aβ42, soluble amyloid precursor protein (sAPP)β, sAPPα, glial-derived neurotrophic factor (GDNF), P-T181-tau, and P-S396-tau were significantly (3- to 20-fold) higher than levels in NDEs for patients and controls. BACE-1 levels also were a mean of 7-fold higher in ADEs than in NDEs from cultured rat type-specific neural cells. Levels of BACE-1 and sAPPβ were significantly higher and of GDNF significantly lower in ADEs of patients with AD than in those of controls, but not significantly different in patients with FTD than in controls. Abundant proteins of the Aβ42 peptide-generating system in ADEs may sustain levels in neurons. ADE cargo proteins may be useful for studies of mechanisms of cellular interactions and effects of BACE-1 inhibitors in AD.-Goetzl, E. J., Mustapic, M., Kapogiannis, D., Eitan, E., Lobach, I. V., Goetzl, L., Schwartz, J. B., Miller, B. L. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease.

show abstract

“…4C). A contributing factor to this discrepancy is likely that BACE-1 is not present in all early endosomes [as evident from double-staining experiments with BACE-1 and endosomal markers (42,58,59)]. In contrast, the positively charged BACE-1 inhibitors will be evenly distributed in the entire endolysosomal space, and consequently, only a fraction of the estimated F endo is colocalized with the target and can exert its effect.…”

Section: Resultsmentioning

confidence: 99%

“…4C). We attribute this to the fact that the compound is evenly distributed across all acidic organelles, whereas only 2% is located in endosomes that also contain the target and its substrate (APP) (42,58,59). Additional studies are needed to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 97%

Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

Mateus

Gordon

Wayne

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F ic ) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery. intracellular drug bioavailability | drug exposure | target engagement | published kinase inhibitor set | MAPK14

show abstract

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

Cited by 18 publications

References 56 publications

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

Cargo proteins of plasma astrocyte‐derived exosomes in Alzheimer's disease

Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery

Contact Info

Product

Resources

About