Transthyretin neuroprotection in Alzheimer's disease is dependent on proteolysis

Silva, Catarina S.; Eira, Jessica; Ribeiro, Carlos A.; Oliveira, Â.; Sousa, Mónica Mendes; Cardoso, Isabel; Liz, Márcia A.

doi:10.1016/j.neurobiolaging.2017.07.002

Cited by 52 publications

(45 citation statements)

References 18 publications

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“…An amyloid–β (Aβ) cleavage protein (Silva et al . ), transthyretin, was shown to be clearly increased in the HIP (139.1%), HYP (135.0%), and AMY (156.7%) (Fig. c).…”

Section: Resultsmentioning

confidence: 85%

“…PKCb, PKCe, and PKCf can function as suppressors of apoptosis, whereas PKCd is pro-apoptotic in function (Sun and Alkon 2012). An amyloid-b (Ab) cleavage protein (Silva et al 2017), transthyretin, was shown to be clearly increased in the HIP (139.1%), HYP (135.0%), and AMY (156.7%) ( Fig. 3c).…”

Section: Resultsmentioning

confidence: 99%

“…Fbxo2, which facilitates the degradation of BACE1 (Atkin et al 2014), was shown to be increased in the HIP. Interestingly, transthyretin, which binds to Ab to inhibit its aggregation and neurotoxicity and acts as an Ab cleavage protein (Silva et al 2017), was shown to be clearly increased in the HIP, HYP, and AMY of the OVX rats. All these data indicated that the PFC and AMY might bear Ab overproduction earlier than the HIP.…”

Section: Discussionmentioning

confidence: 97%

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

Fang

Zeng

et al. 2018

Journal of Neurochemistry

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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.

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“…An amyloid–β (Aβ) cleavage protein (Silva et al . ), transthyretin, was shown to be clearly increased in the HIP (139.1%), HYP (135.0%), and AMY (156.7%) (Fig. c).…”

Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

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

Fang

Zeng

et al. 2018

Journal of Neurochemistry

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“…Furthermore, A β (1–28) holds the residues that chelate metal ions 31 and that can mediate the interaction between TTR and A β . It is not known if TTR binds the entire sequence of A β or only the fragments of A β cleaved by TTR 6 , 42 , but the segment 1–28 of A β is exposed in amyloid fibrils of A β (1–42) 43 .…”

Section: Discussionmentioning

confidence: 99%

Copper mediated amyloid-β binding to Transthyretin

Ciccone

Fruchart-Gaillard

Mourier

et al. 2018

Sci Rep

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Transthyretin (TTR), a homotetrameric protein that transports thyroxine and retinol both in plasma and in cerebrospinal (CSF) fluid provides a natural protective response against Alzheimer’s disease (AD), modulates amyloid-β (Aβ) deposition by direct interaction and co-localizes with Aβ in plaques. TTR levels are lower in the CSF of AD patients. Zn2+, Mn2+ and Fe2+ transform TTR into a protease able to cleave Aβ. To explain these activities, monomer dissociation or conformational changes have been suggested. Here, we report that when TTR crystals are exposed to copper or iron salts, the tetramer undergoes a significant conformational change that alters the dimer-dimer interface and rearranges residues implicated in TTR’s ability to neutralize Aβ. We also describe the conformational changes in TTR upon the binding of the various metal ions. Furthermore, using bio-layer interferometry (BLI) with immobilized Aβ(1–28), we observe the binding of TTR only in the presence of copper. Such Cu2+-dependent binding suggests a recognition mechanism whereby Cu2+ modulates both the TTR conformation, induces a complementary Aβ structure and may participate in the interaction. Cu2+-soaked TTR crystals show a conformation different from that induced by Fe2+, and intriguingly, TTR crystals grown in presence of Aβ(1–28) show different positions for the copper sites from those grown its absence.

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“…In vitro, the proteolytically active form of TTR is able to cleave Aβ peptides as well as their aggregates. The resulting peptides show lower amyloidogenic potential than that of the full-length peptide [65,87]. Nevertheless, it is necessary to determine whether this proteolytic activity is relevant for neuroprotection in vivo.…”

Section: Mechanisms Involved In Transthyretin Neuroprotection In Alzhmentioning

confidence: 99%

Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer’s Disease

Gião

Saavedra

Cotrina³

et al. 2020

IJMS

Self Cite

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Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding to the retinol-binding protein), in these fluids. Still, this protein has managed to stay in the spotlight as it has been assigned new and varied functions. In this review, we cover knowledge on novel TTR functions and the cellular pathways involved, spanning from neuroprotection to vascular events, while emphasizing its involvement in Alzheimer’s disease (AD). We describe details of TTR as an amyloid binding protein and discuss its interaction with the amyloid Aβ peptides, and the proposed mechanisms underlying TTR neuroprotection in AD. We also present the importance of translating advances in the knowledge of the TTR neuroprotective role into drug discovery strategies focused on TTR as a new target in AD therapeutics.

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Transthyretin neuroprotection in Alzheimer's disease is dependent on proteolysis

Cited by 52 publications

References 18 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

Copper mediated amyloid-β binding to Transthyretin

Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer’s Disease

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