Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer’s Disease Neuropathology and Genetics
Open accessAbstract
The single nucleotide polymorphisms rs35349669 and rs10933431 within Inositol Polyphosphate-5-Phosphatase D (INPP5D) are strongly associated with Alzheimer’s Disease risk. To better understand INPP5D expression in the brain, we investigated INPP5D isoform expression as a function of rs35349669 and rs10933431, as well as Alzheimer’s disease neuropathology, by qPCR and isoform-specific primers. In addition, INPP5D allelic expression imbalance was evaluated relative to rs1141328 within exon 1. Expression of INPP5D isoforms associated with transcription start sites in exon 1 and intron 14 was increased in individuals with high Alzheimer’s disease neuropathology. In addition, a novel variant with 47bp lacking from exon 12 increased expression in Alzheimer’s Disease brains, accounting for 13% of total INPP5D expression, and was found to undergo nonsense-mediated decay. Although inter-individual variation obscured a possible polymorphism effect on INPP5D isoform expression as measured by qPCR, rs35349669 was associated with rs1141328 allelic expression imbalance, suggesting that rs35349669 is significantly associated with full-length INPP5D isoform expression. In summary, expression of INPP5D isoforms with start sites in exon 1 and intron 14 are increased in brains with high Alzheimer’s Disease neuropathology, a novel isoform lacking the phosphatase domain was significantly increased with the disease, and the polymorphism rs35349669 correlates with allele-specific full-length INPP5D expression.
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RNA expression data from human brain tissue reveal the presence of isoforms of INPP5D that encode truncated SHIP1 that lacks phosphatase domain.
“Intriguingly, RNA expression data from human brain tissue reveal the presence of isoforms of INPP5D that encode truncated SHIP1 that lacks phosphatase domain12.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [12]
AD risk SNPs at the INPP5D locus are intronic and it is unclear how they influence INPP5D levels.
“AD risk SNPs at the INPP5D locus are intronic and it is unclear how they influence INPP5D levels11,12.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [12]
Another group reported an increase in transcripts encoding truncated forms of SHIP1 that lack the phosphatase domain in AD brain tissue.
“another group reported an increase in transcripts encoding truncated forms of SHIP1 that lack the phosphatase domain in AD brain tissue12.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [12]
A recent study found an increase in expression of INPP5D isoforms in the AD brain, with increased expression of a truncated isoform that lacks the phosphatase domain.
“While they also found an increase in the expression of INPP5D isoforms in the AD brain, the expression of a truncated isoform that lacks the phosphatase domain was increased, suggesting that the increase in INPP5D expression may not necessarily lead to increased SHIP1 activity [171].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [171]
Investigation of AD-associated SNPs in INPP5D did not reveal a clear SNP effect on overall INPP5D expression.
“Of note, the investigation of AD-associated SNPs in INPP5D in this study did not reveal a clear SNP effect on overall INPP5D expression [171].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [171]
An increase in INPP5D expression may not necessarily lead to increased SHIP1 activity.
“the expression of a truncated isoform that lacks the phosphatase domain was increased, suggesting that the increase in INPP5D expression may not necessarily lead to increased SHIP1 activity [171].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [171]
RNA levels of INPP5D are elevated in Alzheimer's disease brain.
“confirm previous findings that RNA levels of INPP5D are elevated in AD brain21.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [20]
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Cites
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263 · cited 1× · see citing works
“TREM2 is a necessary activator of the DAM transcriptional profile [38], and early in the disease is beneficial by increasing microglial proliferation, association with amyloid plaques, and reduction of amyloid burden in the brain ([42,43], and reviewed in [44]).”
BackgroundSingle cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Olah, M., Menon, V., Habib, N., Taga, M. F., Ma, Y., Yung, C. J., Cimpean, M., Khairallah, A., Coronas-Samano, G., Sankowski, R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19737-2 · Cited by 722 · see citing works
Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship
Nelson, P. T., Braak, H., & Markesbery, W. R. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181919a48 · Cited by 643 · see citing works
Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710311114 · Cited by 517 · cited 1× · see citing works
“However, the role of TREM2 late in the disease is less clear, where TREM2 activation can ameliorate or exacerbate disease depending on the murine model [13,42,45,46].”
BackgroundThe identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology
Lee, S.-H., Meilandt, W. J., Xie, L., Gandham, V. D., Ngu, H., Barck, K. H., Rezzonico, M. G., Imperio, J., Lalehzadeh, G., Huntley, M. A., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.02.010 · Cited by 300 · see citing works
Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration
Gratuze, M., Leyns, C. E. G., Sauerbeck, A. D., St-Pierre, M.-K., Xiong, M., Kim, N., Serrano, J. R., Tremblay, M.-È., Kummer, T. T., Colonna, M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci138179 · Cited by 252 · see citing works
TREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191 · see citing works
Genetics ignite focus on microglial inflammation in Alzheimer’s disease
Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., LaDu, M. J., Fardo, D. W., Rebeck, G. W., & Estus, S. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0048-1 · Cited by 161 · see citing works
Self-citationSayed, F. A., Kodama, L., Fan, L., Carling, G. K., Udeochu, J. C., Le, D., Li, Q., Zhou, L., Wong, M. Y., Horowitz, R., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe3947 · Cited by 155 · cited 1× · see citing works
“The ADassociated loss-of-function R47H variant of TREM2 increases proinflammatory signatures of microglia and hyperactivation of AKT in AD individuals and in a tauopathy mouse model [11].”
BackgroundCastranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74 · see citing works
<i>INPP5D</i> deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease
Lin, P. B., Tsai, A. P., Soni, D., Lee‐Gosselin, A., Moutinho, M., Puntambekar, S. S., Landreth, G. E., Lamb, B. T., & Oblak, A. L. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12849 · Cited by 54 · see citing works
Flagged first, then by citations
Research works printed but not linked: 34
- [1]Gatz M. Reynolds C.A. Fratiglioni L. Johansson B. Mortimer J.A. Berg S. Fiske A. Pedersen N.L. Role of genes and environments for explaining Alzheimer disease Arch. Gen. Psychiatry 2006 63 168 174 10.1001/archpsyc.63.2.168 16461860 · DOI · Paper page
- [2]Karch C.M. Jeng A.T. Nowotny P. Cady J. Cruchaga C. Goate A.M. Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains PLoS ONE 2012 7 e50976 10.1371/journal.pone.0050976 23226438 PMC3511432 · DOI · Paper page
- [3]Yoshino Y. Yamazaki K. Ozaki Y. Sao T. Yoshida T. Mori T. Mori Y. Ochi S. Iga J.I. Ueno S.I. INPP5D mRNA Expression and Cognitive Decline in Japanese Alzheimer’s Disease Subjects J. Alzheimers Dis. 2017 58 687 694 10.3233/JAD-161211 28482637 · DOI · Paper page
- [4]Wightman D.P. Jansen I.E. Savage J.E. Shadrin A.A. Bahrami S. Holland D. Rongve A. Borte S. Winsvold B.S. Drange O.K. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease Nat. Genet. 2021 53 1276 1282 10.1038/s41588-021-00921-z 34493870 PMC10243600 · DOI · Paper page
- [6]Zhang J. An X. Han Y. Ma R. Yang K. Zhang L. Chi J. Li W. Llobet -Navas D. Xu Y. Overexpression of JARID1B promotes differentiation via SHIP1/AKT signaling in human hypopharyngeal squamous cell carcinoma Cell Death Dis. 2016 7 e2358 10.1038/cddis.2016.262 27584795 PMC5059865 · DOI
- [8]Efthymiou A.G. Goate A.M. Late onset Alzheimer’s disease genetics im plicates microglial pathways in disease risk Mol. Neurodegener. 2017 12 43 10.1186/s13024-017-0184-x 28549481 PMC5446752 · DOI · Paper page
- [10]Song W.M. Colonna M. The Microglial Response to Neurodegenerative Disease Adv. Immunol. 2018 139 1 50 10.1016/bs.ai.2018.04.002 30249333 · DOI
- [12]Pereira J.B. Janelidze S. Strandberg O. Whelan C.D. Zetterberg H. Blennow K. Palmqvist S. Stomrud E. Mattsson-Carlgren N. Hansson O. Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer’s disease pathology Nat. Aging 2022 2 1138 1144 10.1038/s43587-022-00310-z PMC10154192 37118533 · DOI
- [13]Jain N. Lewis C.A. Ulrich J.D. Holtzman D.M. Chronic TREM2 activation exacerbates Abeta-associated tau seeding and spreading J. Exp. Med. 2023 220 10.1084/jem.20220654 PMC9559604 36219197 · DOI · Paper page
- [14]Jansen I.E. Savage J.E. Watanabe K. Bryois J. Williams D.M. Steinberg S. Sealock J. Karlsson I.K. Hagg S. Athanasiu L. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk Nat. Genet. 2019 51 404 413 10.1038/s41588-018-0311-9 30617256 PMC6836675 · DOI · Paper page
- [15]Lambert J.C. Ibrahim-Verbaas C.A. Harold D. Naj A.C. Sims R. Bellenguez C. DeStafano A.L. Bis J.C. Beecham G.W. Grenier-Boley B. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease Nat. Genet. 2013 45 1452 1458 10.1038/ng.2802 24162737 PMC3896259 · DOI · Paper page
- [16]Van Cauwenberghe C. Van Broeckhoven C. Sleegers K. The genetic landscape of Alzheimer disease: Clinical implications and perspectives Genet. Med. 2016 18 421 430 10.1038/gim.2015.117 26312828 PMC4857183 · DOI · Paper page
- [17]Peng Q. Malhotra S. Torchia J.A. Kerr W.G. Coggeshall K.M. Humphrey M.B. TREM2—and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1 Sci. Signal 2010 3 ra38 10.1126/scisignal.2000500 20484116 PMC2900152 · DOI · Paper page
- [18]Li C. Zhao B. Lin C. Gong Z. An X. TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF-kappaB signaling Cell Biol. Int. 2019 43 360 372 10.1002/cbin.10975 29663649 PMC7379930 · DOI
- [19]Mondal S. Subramanian K.K. Sakai J. Bajrami B. Luo H.R. Phosphoinositide lipid phosphatase SHIP1 and PTEN coordinate to regulate cell migration and adhesion Mol. Biol. Cell 2012 23 1219 1230 10.1091/mbc.e11-10-0889 22323291 PMC3315799 · DOI
- [20]Wang S. Sudan R. Peng V. Zhou Y. Du S. Yuede C.M. Lei T. Hou J. Cai Z. Cella M. TREM2 drives microglia response to amyloid-beta via SYK-dependent and -independent pathways Cell 2022 185 4153 4169 10.1016/j.cell.2022.09.033 36306735 PMC9625082 · DOI · Paper page
- [21]Iguchi A. Takatori S. Kimura S. Hori Y. Sasaki J. Saito T. Saido T.C. Ikezu T. Takai T. Sasaki T. INPP5D Modulates TREM2 Loss-of-Function Phenotypes in a Mouse Model of Alzheimer Disease Neuron 2021 61 3844721 10.2139/ssrn.3844721 · DOI
- [23]Machiela M.J. Chanock S.J. LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants Bioinformatics 2015 31 3555 3557 10.1093/bioinformatics/btv402 26139635 PMC4626747 · DOI · Paper page
- [24]Grear K.E. Ling I.F. Simpson J.F. Furman J.L. Simmons C.R. Peterson S.L. Schmitt F.A. Markesbery W.R. Liu Q. Crook J.E. Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain Mol. Neurodegener. 2009 4 46 10.1186/1750-1326-4-46 19889229 PMC2776013 · DOI · Paper page
- [25]Malik M. Chiles J. 3rd Xi H.S. Medway C. Simpson J. Potluri S. Howard D. Liang Y. Paumi C.M. Mukherjee S. Genetics of CD33 in Alzheimer’s disease and acute myeloid leukemia Hum. Mol. Genet. 2015 24 3557 3570 10.1093/hmg/ddv092 25762156 PMC4498153 · DOI
- [26]Shaw B.C. Katsumata Y. Simpson J.F. Fardo D.W. Estus S. Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer’s Disease Risk Reveal a Potential Role for SIGLEC14 Genes 2021 12 1008 10.3390/genes12071008 34208838 PMC8303736 · DOI
- [27]Shaw B.C. Snider H.C. Turner A.K. Zajac D.J. Simpson J.F. Estus S. An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain is Expressed in Human Brain J. Alzheimers Dis. 2022 87 1647 1657 10.3233/JAD-215602 35527547 PMC9335121 · DOI
- [28]Pievani M. Rasser P.E. Galluzzi S. Benussi L. Ghidoni R. Sabattoli F. Bonetti M. Binetti G. Thompson P.M. Frisoni G.B. Mapping the effect of APOE epsilon4 on gray matter loss in Alzheimer’s disease In Vivo Neuroimage 2009 45 1090 1098 10.1016/j.neuroimage.2009.01.009 19349226 PMC2739903 · DOI
- [29]Tan R.H. Pok K. Wong S. Brooks D. Halliday G.M. Kril J.J. The pathogenesis of cingulate atrophy in behavioral vari ant frontotemporal dementia and Alzheimer’s disease Acta Neuropathol. Commun. 2013 1 30 10.1186/2051-5960-1-30 24252534 PMC3893385 · DOI
- [31]Malik M. Simpson J.F. Parikh I. Wilfred B.R. Fardo D.W. Nelson P.T. Estus S. CD33 Alzheimer’s risk -altering polymorphism, CD33 expression, and exon 2 splicing J. Neurosci. 2013 33 13320 13325 10.1523/JNEUROSCI.1224-13.2013 23946390 PMC3742922 · DOI · Paper page
- [32]Parikh I. Fardo D.W. Estus S. Genetics of PICALM expression and Alzheimer’s disease PLoS ONE 2014 9 e91242 10.1371/journal.pone.0091242 24618820 PMC3949918 · DOI
- [33]Turner A.K. Shaw B.C. Simpson J.F. Estus S. Identification and Quantitation of Novel ABI3 Isoforms Relative to Alzheimer’s Disease Genetics and Neuropathology Genes 2022 13 1607 10.3390/genes13091607 36140776 PMC9498898 · DOI · Paper page
- [34]Parikh I. Medway C. Younkin S. Fardo D.W. Estus S. An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALM isoform Mol. Neurodegener. 2014 9 32 10.1186/1750-1326-9-32 25169757 PMC4150683 · DOI
- [35]Sambrook J. Russell D.W. Isolation of DNA fragments from polyacrylamide gels by the crush and soak method CSH Protoc. 2006 2006 1 6 10.1101/pdb.prot2936 22485254 · DOI
- [36]Tsai A.P. Lin P.B. Dong C. Moutinho M. Casali B.T. Liu Y. Lamb B.T. Landreth G.E. Oblak A.L. Nho K. INPP5D expression is associated with risk for Alzheimer’s disease and induced by plaque-associated microglia Neurobiol. Dis. 2021 153 105303 10.1016/j.nbd.2021.105303 33631273 PMC8082515 · DOI · Paper page
- [37]Consortium G.T. The GTEx Consortium atlas of genetic regulatory effects across human tissues Science 2020 369 1318 1330 10.1126/science.aaz1776 32913098 PMC7737656 · DOI · Paper page
- [38]Keren-Shaul H. Spinrad A. Weiner A. Matcovitch-Natan O. Dvir-Szternfeld R. Ulland T.K. David E. Baruch K. Lara-Astaiso D. Toth B. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease Cell 2017 169 1276 1290 10.1016/j.cell.2017.05.018 28602351 · DOI · Paper page
- [40]Huang K.L. Marcora E. Pimenova A.A. Di Narzo A.F. Kapoor M. Jin S.C. Harari O. Bertelsen S. Fairfax B.P. Czajkowski J. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease Nat. Neurosci. 2017 20 1052 1061 10.1038/nn.4587 28628103 PMC5759334 · DOI · Paper page
- [41]He L. Loika Y. Kulminski A.M. Allele-specific analysis reveals exon- and cell-type-specific regulatory effects of Alzheimer’s disease-associated genetic variants Transl. Psychiatry 2022 12 163 10.1038/s41398-022-01913-1 35436980 PMC9016079 · DOI
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Sorted by citations
Terzioglu, G., & Young-Pearse, T. L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00674-9 · Cited by 95 · see citing works
INPP5D regulates inflammasome activation in human microglia
Chou, V., Pearse, R. V., Aylward, A. J., Ashour, N., Taga, M., Terzioglu, G., Fujita, M., Fancher, S. B., Sigalov, A., Benoit, C. R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42819-w · Cited by 79 · see citing works
INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia
Terzioglu, G., Karp, E. S., Heuer, S. E., Chadarevian, J. P., Ahsan, F. M., Haage, V. C., Davtyan, H., Fogo, G. M., Curle, A. J., Ashour, N., et al. (2025) · doi:10.1101/2025.10.27.684632 · Cited by 3 · see citing works
- Authors
- Zajac, D. J., Simpson, J., Zhang, E., Parikh, I., & Estus, S.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Estus, Steven
- Venue
- Genes
- Publisher
- MDPI AG
- Published
- 2023-03-21
- Volume
- 14
- Issue
- 3
- Pages
- 763
- ISSN
- 2073-4425 (ISSN-L)
- PMC
- PMC10048252
- OpenAlex
- W4328129300
- Cited by
- 18
- References
- 12
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 6
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Genes (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- NIH (RF1AG059717, R21AG068370, GM118292-03, 5P30AG028383)
- The University of Kentucky Alzheimer’s disease center (RF1AG059717, R21AG068370, GM118292-03, 5P30AG028383)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- INPP5D, Alzheimer's disease, isoform expression, single nucleotide polymorphisms, allelic expression imbalance, nonsense-mediated mRNA decay, phosphatase domain, human brain, neuropathology, transcription start sites
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Alleles, Alzheimer Disease, Brain, Humans, Protein Isoforms, Polymorphism, Single Nucleotide
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