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Article ; Online: Alzheimer's genes in microglia: a risk worth investigating.

Sudwarts, Ari / Thinakaran, Gopal

2023 Volume 18, Issue 1, Page(s) 90

Abstract: Despite expressing many key risk genes, the role of microglia in late-onset Alzheimer's disease pathophysiology is somewhat ambiguous, with various phenotypes reported to be either harmful or protective. Herein, we review some key findings from clinical ... ...

Abstract	Despite expressing many key risk genes, the role of microglia in late-onset Alzheimer's disease pathophysiology is somewhat ambiguous, with various phenotypes reported to be either harmful or protective. Herein, we review some key findings from clinical and animal model investigations, discussing the role of microglial genetics in mediating perturbations from homeostasis. We note that impairment to protective phenotypes may include prolonged or insufficient microglial activation, resulting in dysregulated metabolomic (notably lipid-related) processes, compounded by age-related inflexibility in dynamic responses. Insufficiencies of mouse genetics and aggressive transgenic modelling imply severe limitations in applying current methodologies for aetiological investigations. Despite the shortcomings, widely used amyloidosis and tauopathy models of the disease have proven invaluable in dissecting microglial functional responses to AD pathophysiology. Some recent advances have brought modelling tools closer to human genetics, increasing the validity of both aetiological and translational endeavours.
MeSH term(s)	Mice ; Humans ; Animals ; Alzheimer Disease/genetics ; Microglia/physiology ; Amyloidosis ; Disease Models, Animal ; Mice, Transgenic
Language	English
Publishing date	2023-11-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-023-00679-4
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Article ; Online: Cinnabarinic Acid-Induced Stanniocalcin 2 Confers Cytoprotection against Alcohol-Induced Liver Injury.

Joshi, Aditya D / Thinakaran, Gopal / Elferink, Cornelis

The Journal of pharmacology and experimental therapeutics

2022 Volume 381, Issue 1, Page(s) 1–11

Abstract: We recently identified upregulation of a novel aryl hydrocarbon receptor (AhR) target gene, stanniocalcin 2 (STC2), by an endogenous AhR agonist, cinnabarinic acid (CA). STC2 is a disulfide-linked homodimeric secreted glycoprotein that plays a role in ... ...

Abstract	We recently identified upregulation of a novel aryl hydrocarbon receptor (AhR) target gene, stanniocalcin 2 (STC2), by an endogenous AhR agonist, cinnabarinic acid (CA). STC2 is a disulfide-linked homodimeric secreted glycoprotein that plays a role in various physiologic processes, including cell metabolism, inflammation, endoplasmic reticulum (ER) and oxidative stress, calcium regulation, cell proliferation, and apoptosis. Our previous studies have confirmed that CA-induced AhR-dependent STC2 expression was able to confer cytoprotection both in vitro and in vivo in response to injury induced by variety of ER/oxidative insults. Here, we used mouse models of chronic and acute ethanol feeding and demonstrated that upregulation of STC2 by CA was critical for cytoprotection. In STC2 knockout mice (STC2
MeSH term(s)	Animals ; Chemical and Drug Induced Liver Injury, Chronic ; Cytoprotection ; Ethanol/toxicity ; Glycoproteins ; Mice ; Oxazines ; Receptors, Aryl Hydrocarbon/genetics
Chemical Substances	Glycoproteins ; Oxazines ; Receptors, Aryl Hydrocarbon ; Ethanol (3K9958V90M) ; cinnabarinic acid (606-59-7) ; teleocalcin (76687-96-2)
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.121.000999
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Article ; Online: Matrix metalloproteinase 13, a new target for therapy in Alzheimer's disease.

Paumier, Jean-Michel / Thinakaran, Gopal

Genes & diseases

2019 Volume 6, Issue 1, Page(s) 1–2

Language	English
Publishing date	2019-02-16
Publishing country	China
Document type	Journal Article
ZDB-ID	2821806-1
ISSN	2352-3042 ; 2352-3042
ISSN (online)	2352-3042
ISSN	2352-3042
DOI	10.1016/j.gendis.2019.02.004
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Article ; Online: Evidence for a clathrin-independent endocytic pathway for APP internalization in the neuronal somatodendritic compartment.

Aow, Jonathan / Huang, Tzu-Rung / Goh, Yeek Teck / Sun, Alfred Xuyang / Thinakaran, Gopal / Koo, Edward H

Cell reports

2023 Volume 42, Issue 7, Page(s) 112774

Abstract: Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) production. Here, we show that ... ...

Abstract	Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) production. Here, we show that somatodendritic APP internalization in primary rodent neurons is not blocked by inhibiting dynamin or mutating the YENPTY motif, in contrast to non-neuronal cell lines. These phenomena, confirmed in induced human neurons under dynamin inhibition, occur during basal conditions and chemical long-term-depression stimulus, pointing to a clathrin-independent internalization pathway for somatodendritic APP. Mutating the YENPTY motif does not alter APP recycling, degradation, or endolysosomal colocalization. However, both dynamin inhibition and the YENPTY mutant significantly decrease secreted Aβ in neurons, suggesting that internalized somatodendritic APP may not constitute a major source of Aβ. Interestingly, like APP, somatodendritic low-density lipoprotein receptor (LDLR) internalization does not require its CME motif. These results highlight intriguing differences in neuronal internalization pathways and refine our understanding of Aβ production and secretion.
MeSH term(s)	Humans ; Amyloid beta-Protein Precursor/metabolism ; Alzheimer Disease/metabolism ; Clathrin/metabolism ; Amyloid beta-Peptides/metabolism ; Neurons/metabolism ; Endocytosis/physiology ; Amyloid Precursor Protein Secretases/metabolism ; Dynamins
Chemical Substances	Amyloid beta-Protein Precursor ; Clathrin ; Amyloid beta-Peptides ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112774
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Article ; Online: Enhanced cleavage of APP by co-expressed Bace1 alters the distribution of APP and its fragments in neuronal and non-neuronal cells.

Aow, Jonathan / Huang, Tzu-Rung / Thinakaran, Gopal / Koo, Edward H

Molecular neurobiology

2022 Volume 59, Issue 5, Page(s) 3073–3090

Abstract: Background: Alzheimer's disease amyloid-beta peptides (Aβ) are generated via sequential cleavage of the amyloid precursor protein (APP) by β-secretase (Bace1) and γ-secretase. Though the precise subcellular location(s) of Bace1-mediated APP cleavage ... ...

Abstract	Background: Alzheimer's disease amyloid-beta peptides (Aβ) are generated via sequential cleavage of the amyloid precursor protein (APP) by β-secretase (Bace1) and γ-secretase. Though the precise subcellular location(s) of Bace1-mediated APP cleavage remains unresolved, current models suggest APP internalization into Bace1-containing endosomes is a critical step. However, direct evidence for this model is lacking, and previous reports that probed the APP/Bace1 interaction (using co-expressed APP and Bace1 differentially labeled with fluorescent protein tags) did not determine if APP fluorescence originated from full-length APP (fl-APP) molecules that had internalized from the cell surface pool. Methods: We adapted the bungarotoxin-ligand (BTX) system to label surface APP and track internalized fluorescent APP/BTX puncta in rodent primary neurons co-expressing fluorescently-tagged Bace1. Subsequently, we employed imaging and biochemical-based approaches to measure N- and C-terminal APP epitope levels in primary neurons, N2a neuroblastoma, and HeLa cell lines. Results: We hypothesized that surface-labeled APP/BTX puncta would, upon internalization, colocalize with fluorescently-tagged Bace1. Unexpectedly, we observed a dramatic loss of internalized APP in co-transfected neurons and ~ 80-90% loss of surface-resident fl-APP, which we also observed in HeLa and N2a cells. Loss of surface fl-APP could be reversed by a Bace1 inhibitor, suggesting that enhanced Bace1-mediated APP cleavage was responsible for the altered processing and mis-sorting. Importantly, in a C-terminally-tagged APP construct, the majority of C-terminal fluorescence was preserved in HeLa cells despite the loss of N-terminal APP signal. This phenomenon was not only recapitulated in cultured neurons, but also showed a progressive disappearance of the APP N-terminal tag, reflecting continual cleavage of fl-APP by Bace1 away from the cell body. Conclusions: Our results strongly suggested that in APP/Bace1 co-expression approaches, there was significant early and aberrant Bace1-mediated APP cleavage that perturbed fl-APP trafficking from the secretory pathway onwards, resulting in a substantial loss of surface fl-APP, which in turn led to a marked reduction in APP internalization. In C-terminally-tagged APP constructs, a large fraction of the APP fluorescence signal therefore likely arose from fluorescently-tagged β-C-terminal-fragment (β-CTF) or downstream proteolytic derivatives instead of fl-APP. Thus, care is needed in interpreting results where APP is detected only with a C-terminal tag in the presence of Bace1 co-expression, and previous findings may need to be reinterpreted if it is unclear whether fl-APP is present in normal physiological levels.
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Aspartic Acid Endopeptidases/metabolism ; HeLa Cells ; Humans ; Neurons/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46)
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-022-02733-6
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Article ; Online: Evidence for a clathrin-independent endocytic pathway for APP internalization in the neuronal somatodendritic compartment

Jonathan Aow / Tzu-Rung Huang / Yeek Teck Goh / Alfred Xuyang Sun / Gopal Thinakaran / Edward H. Koo

Cell Reports, Vol 42, Iss 7, Pp 112774- (2023)

2023

Abstract: Summary: Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) production. Here, we show that ... ...

Abstract	Summary: Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) production. Here, we show that somatodendritic APP internalization in primary rodent neurons is not blocked by inhibiting dynamin or mutating the YENPTY motif, in contrast to non-neuronal cell lines. These phenomena, confirmed in induced human neurons under dynamin inhibition, occur during basal conditions and chemical long-term-depression stimulus, pointing to a clathrin-independent internalization pathway for somatodendritic APP. Mutating the YENPTY motif does not alter APP recycling, degradation, or endolysosomal colocalization. However, both dynamin inhibition and the YENPTY mutant significantly decrease secreted Aβ in neurons, suggesting that internalized somatodendritic APP may not constitute a major source of Aβ. Interestingly, like APP, somatodendritic low-density lipoprotein receptor (LDLR) internalization does not require its CME motif. These results highlight intriguing differences in neuronal internalization pathways and refine our understanding of Aβ production and secretion.
Keywords	CP: Cell biology ; CP: Neuroscience ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Correction: Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts.

De Rossi, Pierre / Buggia-Prévot, Virginie / Clayton, Benjamin L L / Vasquez, Jared B / van Sanford, Carson / Andrew, Robert J / Lesnick, Ruben / Botté, Alexandra / Deyts, Carole / Salem, Someya / Rao, Eshaan / Rice, Richard C / Parent, Angèle / Kar, Satyabrata / Popko, Brian / Pytel, Peter / Estus, Steven / Thinakaran, Gopal

Molecular neurodegeneration

2023 Volume 18, Issue 1, Page(s) 72

Language	English
Publishing date	2023-10-02
Publishing country	England
Document type	Published Erratum
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-023-00662-z
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Article ; Online: Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis.

Ulku, Irem / Liebsch, Filip / Akerman, S Can / Schulz, Jana F / Kulic, Luka / Hock, Christoph / Pietrzik, Claus / Di Spiezio, Alessandro / Thinakaran, Gopal / Saftig, Paul / Multhaup, Gerhard

Scientific reports

2023 Volume 13, Issue 1, Page(s) 2216

Abstract: The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby ...

Abstract	The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby it degrades longer Aβ peptides into a non‑toxic Aβ34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1/APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and Aβ34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by ~ 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased Aβ34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Aβ34 levels. To align the role of γ-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-γ-secretase as the main γ-secretase that generates Aβ40 and Aβ42 peptides serving as substrates for BACE1's amyloidolytic cleavage to generate Aβ34.
MeSH term(s)	Mice ; Animals ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Mice, Transgenic ; Alzheimer Disease/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Amyloid beta-Peptides/metabolism ; Homeostasis
Chemical Substances	Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Amyloid beta-Protein Precursor ; Amyloid beta-Peptides ; Bace1 protein, mouse (EC 3.4.23.46)
Language	English
Publishing date	2023-02-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-28846-z
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Article ; Online: Significance of transcytosis in Alzheimer's disease: BACE1 takes the scenic route to axons.

Buggia-Prévot, Virginie / Thinakaran, Gopal

BioEssays : news and reviews in molecular, cellular and developmental biology

2015 Volume 37, Issue 8, Page(s) 888–898

Abstract: Neurons have developed elaborate mechanisms for sorting of proteins to their destination in dendrites and axons as well as dynamic local trafficking. Recent evidence suggests that polarized axonal sorting of β-site converting enzyme 1 (BACE1), a type I ... ...

Abstract	Neurons have developed elaborate mechanisms for sorting of proteins to their destination in dendrites and axons as well as dynamic local trafficking. Recent evidence suggests that polarized axonal sorting of β-site converting enzyme 1 (BACE1), a type I transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis, entails an unusual journey. In hippocampal neurons, BACE1 internalized from dendrites is conveyed in recycling endosomes via unidirectional retrograde transport towards the soma and sorted to axons where BACE1 becomes enriched. In comparison to other transmembrane proteins that undergo transcytosis or elimination in somatodendritic compartment, vectorial transport of internalized BACE1 in dendrites is unique and intriguing. Dysfunction of protein transport contributes to pathogenesis of AD and other neurodegenerative diseases. Therefore, characterization of BACE1 transcytosis is an important addition to the multiple lines of evidence that highlight the crucial role played by endosomal trafficking pathway as well as axonal sorting mechanisms in AD pathogenesis.
MeSH term(s)	Alzheimer Disease/enzymology ; Alzheimer Disease/pathology ; Amyloid Precursor Protein Secretases/metabolism ; Animals ; Aspartic Acid Endopeptidases/metabolism ; Axonal Transport ; Axons/enzymology ; Endocytosis ; Endosomes/enzymology ; Humans ; Transcytosis
Chemical Substances	Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46)
Language	English
Publishing date	2015-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.201500019
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Zs.A 2024: Show issues

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Article ; Online: Sorting the role of SORLA in Alzheimer's disease.

Buggia-Prévot, Virginie / Thinakaran, Gopal

Science translational medicine

2014 Volume 6, Issue 223, Page(s) 223fs8

Abstract: Cell culture and mouse models unravel how the SORLA receptor negatively regulates β-amyloid (Caglayan et al.). ...

Abstract	Cell culture and mouse models unravel how the SORLA receptor negatively regulates β-amyloid (Caglayan et al.).
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Humans ; LDL-Receptor Related Proteins/metabolism ; Lysosomes/metabolism ; Membrane Transport Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; LDL-Receptor Related Proteins ; Membrane Transport Proteins ; SORL1 protein, human
Language	English
Publishing date	2014-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.3008562
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