INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model

Iguchi, Akihiro; Takatori, Sho; Kimura, Shingo; Muneto, Hiroki; Wang, Kai; Etani, Hayato; Ito, Genta; Sato, Haruaki; Hori, Yukiko; Sasaki, Junko; Saito, Takashi; Saido, Takaomi C.; Ikezu, Tsuneya; Takai, Toshiyuki; Sasaki, Takehiko; Tomita, Taisuke

doi:10.1016/j.isci.2023.106375

Cited by 37Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsInflammasome and immune disorders

INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model

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Iguchi, Akihiro, Takatori, Sho, Kimura, Shingo, Muneto, Hiroki, Wang, Kai, Etani, Hayato, Ito, Genta, Sato, Haruaki +8 more·2023·iScience

DOI 10.1016/j.isci.2023.106375PMC PMC10074152

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Abstract

The genetic associations of TREM2 loss-of-function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid β (Aβ) plaques, impair their transcriptional response to Aβ, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear. In this study, we investigated the pathological role of another AD risk gene, INPP5D , encoding a phosphoinositide PI(3,4,5)P 3 phosphatase expressed in microglia. In a Tyrobp -deficient TREM2 loss-of-function mouse model, Inpp5d haplodeficiency restored the association of microglia with Aβ plaques, partially restored plaque compaction, and astrogliosis, and reduced phosphorylated tau + dystrophic neurites. Mechanistic analyses suggest that TREM2/TYROBP and INPP5D exert opposing effects on PI(3,4,5)P 3 signaling pathways as well as on phosphoproteins involved in the actin assembly. Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aβ toxicity, thereby modulates Aβ-dependent pathological conversion of tau.

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Microglial activation and actin remodeling are processes that can be mediated by Inpp5d.
“which are both processes that can be mediated by Inpp5d. 6 , 20”
From Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [20]
Iguchi et al. found that at 9 months of age, Inpp5d depletion increased microgliosis and plaque engagement in male mice.
“At 9 months of age, Inpp5d depletion increased microgliosis and plaque engagement in male mice.”
From Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [20]
Previous studies of Inpp5d in AD have employed APP transgenic or knock-in models.
“Previous studies of Inpp5d in AD have employed APP transgenic or knock‐in models to determine the effect of Inpp5d depletion on amyloid pathology. 18 , 19 , 20 , 49”
From Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [20]
Iguchi et al. provides evidence that Inpp5d loss increases glial engagement with plaques, as also observed by both Lin et al. and Samuels et al.
“Iguchi et al. provides evidence that Inpp5d loss increases glial engagement with plaques, as also observed by both Lin et al. and Samuels et al.”
From Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [20]
Inpp5d haplodeficiency in addition to Tyrobp deficiency partially rescued the impairments in microglial response to Aβ plaques and plaque compaction observed with Tyrobp deficiency alone in Inpp5d+/−;Tyrobp−/−App knock-in mice.
“Another study generated an Inpp5d+/−;Tyrobp−/−App knock-in mouse model and found that Inpp5d haplodeficiency in addition to Tyrobp deficiency partially rescued the impairments in microglial response to Aβ plaques and plaque compaction observed with Tyrobp deficiency alone [165].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [165]

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Authors: Iguchi, A., Takatori, S., Kimura, S., Muneto, H., Wang, K., Etani, H., Ito, G., Sato, H., Hori, Y., Sasaki, J., Saito, T., Saido, T. C., Ikezu, T., Takai, T., Sasaki, T., & Tomita, T.
Affiliations: The University of Tokyo (JP)
Teikyo University (JP)
Tokyo Medical and Dental University (JP)
RIKEN Center for Brain Science (JP)
Mayo Clinic in Florida (US)
Tohoku University (JP)
Corresponding author: Tomita, Taisuke
ORCID: Takatori, Sho
Wang, Kai
Ito, Genta
Sato, Haruaki
Hori, Yukiko
Sasaki, Junko
Saito, Takashi
Saido, Takaomi C.
Ikezu, Tsuneya
Takai, Toshiyuki
Sasaki, Takehiko
Tomita, Taisuke
Venue: iScience
Publisher: Elsevier BV
Published: 2023-04
Volume: 26
Issue: 4
Pages: 106375
ISSN: 2589-0042 (ISSN-L)
DOI: 10.1016/j.isci.2023.106375
PMC: PMC10074152
OpenAlex: W4324100576
Semantic Scholar: a97865f5bc080f37c175cde3006d3f26b0a0db39
Cited by: 37
References: 99
Citations by year: 2026: 10 · 2025: 9 · 2024: 11 · 2023: 7
FWCI: 5.33
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: iScience (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
PubMed Central (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Funders: Mitsubishi Foundation
Biogen
University of Tokyo
Uehara Memorial Foundation
Juntendo University
Japan Agency for Medical Research and Development (JP20dm0107056, JP20dm0207073)
Nagoya City University
Japan Society for the Promotion of Science (15H02492, 19H01015, 19K07080)
Japan Science and Technology Agency (JPMJMS2024)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: INPP5D, TREM2, TYROBP, beta-amyloidosis, microglia, tau pathology, actin cytoskeleton, phosphoproteins, neuroinflammation, Alzheimer's disease

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INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model

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