Does AD Risk Gene INPP5D Leave Lysosomes With a Leak?

Common variants in the phosphoinositol phosphatase INPP5D are linked to an increased risk of late-onset Alzheimer’s disease, but no one is quite sure why. Recent work suggests that depleting INPP5D in microglia activates the inflammasome and spurs secretion of proinflammatory cytokines. Scientists now blame faulty lysosomes. In a preprint uploaded to bioRxiv on October 27, Tracy Young-Pearse at Brigham and Women’s Hospital, Boston, and colleagues claim that without INPP5D, lysosomes in microglia spring leaks, spilling proteases into the cytosol and setting off inflammatory signaling.

  • In microglia, knocking out INPP5D impairs autophagy.
  • Lysosomes release proteases into the cytosol.
  • In turn, this might trigger the inflammasome.

The scientists used two different human iPSC-derived microglial cell lines. They did not always behave the same way, making the results a bit tricky to interpret.

“The data highlight real biological variability across donor-derived iPSC microglia, which underscores the importance of isogenic controls when interpreting AD-relevant phenotypes,” said Adamantios Mamais of the University of Florida, Gainesville (comment below).

Many variants linked to risk for late-onset Alzheimer’s, including INPP5D, are found in genes that are highly expressed in microglia. INPP5D encodes Src homology 2 (SH2) domain–containing inositol polyphosphate 5-phosphatase 1, a mouthful that can thankfully be abbreviated to SHIP1. The phosphatase is best known for counterbalancing the activity of phosphoinositol-3 kinase. When cell-surface receptors are activated, PI3K springs into action, adding phosphate groups to membrane lipids to create docking sites for immune signaling proteins. SHIP1 reverses this step, trimming those phosphate groups away to keep signaling pathways in check.

Scientists are trying to figure out whether SHIP1 levels, or function, are altered by AD risk variants. Steven Estus and colleagues at the University of Kentucky, Lexington, found that one risk SNP modestly boosted SHIP1 expression, and that this tracked with Alzheimer’s pathology (Zajac et al., 2023). Likewise, researchers led by Adrian Oblak and Kwangsik Nho at Indiana University School of Medicine, Indianapolis, reported elevated INPP5D mRNA in AD brain (Tsai et al., 2021).

So, more INPP5D is bad for the brain? Not so fast. In earlier mass spectrometry work, Young-Pearse and colleagues found that while AD brain had more SHIP1 overall, its phosphatase domains petered out, while C-termini abounded. Young-Pearse and colleagues concluded that much of SHIP1 in AD brain is truncated and inactive (Chou et al., 2023; Dec 2023 news).

In that same study, the scientists asked what happens when cells lose SHIP1 activity. They generated microglia from iPSCs derived from donors enrolled in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), using a differentiation protocol developed by Mathew Blurton-Jones and colleagues (McQuade et al., 2018). Using CRISPR/Cas9, they then knocked out one copy of the INPP5D gene to mimic a partial depletion. Lowering INPP5D levels boosted several lysosomal-associated proteins, including cathepsin A, LAMP1, and TMEM106B, as shown by mass spectrometry. The cells also secreted more of the cytokines IL-1β and IL-18 into the culture medium, an effect dampened by an inflammasome inhibitor, suggesting loss of SHIP1 activates the inflammasome.

Since then Young-Pearse and colleagues have built on this work to investigate if lysosomal dysfunction underlies the rise in inflammatory signaling. First author Gizem Terzioglu and colleagues used microglia derived from two different ROSMAP donors, a man and a woman, neither of whom had neurological issues at the time of donation or death.

Terzioglu and colleagues began by examining lysosomal degradation in SHIP1-deficient microglia. They incubated the cells with Red BSA, which fluoresces when cleaved by lysosomal proteases. Microglia lacking one INPP5D allele fluoresced weakly, suggesting they degraded endocytosed material poorly.

To further gauge lysosomal function, Terzioglu stained the cells with BODIPY 493/503, which lights up lipids. Lipid droplets are a key target of autophagy in microglia, and if not cleared, they impair phagocytosis (Feb 2025 news; Wu et al., 2025). Indeed, compared to their wild-type counterparts, cells with only one working copy of INPP5D were chock-full of lipid droplets (image below).

Not SHIP1 Shape. Microglia (red), accumulated lipids (green) when one copy of INPP5D was missing (right). [Courtesy of Terzioglu et al., 2025 bioRxiv.]

To dig deeper into how lysosomes might be going awry, the scientists stained for the lysosomal protease cathepsin B. On western blots, the ratio of cathepsin B to the lysosomal marker LAMP1 was higher in INPP5D-deficient cells, suggesting they had more of the protease. But on immunocytochemistry (ICC) analysis the area in the cell covered by fluorescent cathepsin B puncta was smaller, though more intense. “We think that the cathepsin B is leaking out of the lysosomes—it is then more diffusely distributed and thus below the limit of detection by eye in the ICC images,” Young-Pearse wrote to Alzforum. It is the cytosolic cathepsin B that rouses the inflammasome, the authors contend.

Catb Out of the Bag. Cathepsin B (purple) in two INPP5D-depleted cell lines (bottom) covers less area than in wild-type cells (top). Has the lysosomal protease escaped into the cytosol? [Courtesy of Terzioglu et al., 2025, bioRxiv.]

The researchers did not directly measure cytosolic cathepsin B or lysosomal permeability. They did test their hypothesis by blocking cathepsin B with a small molecule. Terzioglu treated wild-type microglia with 3AC, which inhibits SHIP1, and with CA-074-Me to block cathepsin B activity. The cells released fewer cytokines than cells treated with the SHIP1 inhibitor alone, suggesting cathepsin B contributes to inflammasome activation.

Put It All Together. Without INPP5D (top, right), lysosomal degradation falters, lipids build up, cathepsin B escapes to stir the inflammasome, and microglia spew cytokines (bottom left). [Courtesy of Terzioglu et al., 2025, bioRxiv.]

John Lukens from the University of Virginia was impressed. “This is a tour de force in defining a molecular mechanism through which INPP5D/SHIP1 regulates inflammasome activation,” he said (comment below). “By revealing a critical role for cathepsin B leakage into the cytosol as the trigger that incites NLRP3 inflammasome activation, they’ve identified a novel molecular player to target in AD.”

Luis Bonet-Ponce of the Ohio State University, Columbus, is less convinced. “It’s an interesting study, but the authors need more data, either by isolating lysosomes and measuring protease activity directly, or by assessing membrane rupture with additional staining, before they can claim they’re leaky,” he told Alzforum.—George R. Heaton

George Heaton is a freelance writer in Durham, North Carolina.

Comments

  1. This is a rigorous and well-designed study that builds beautifully on the group’s earlier work and fills an important mechanistic gap. The proposed mechanism of how SHIP1 loss impairs endosomal maturation and lysosomal integrity, leading to cathepsin leakage and NLRP3 activation, aligns well with the broader literature on PI3K pathway regulation and organelle stress as endogenous triggers of inflammation. What I find particularly compelling is how these lysosomal defects tie together two major AD-relevant processes: impaired Aβ degradation and increased susceptibility to inflammasome activation. 

    This convergence is biologically meaningful. At the same time, the data highlight real biological variability across donor-derived iPSC microglia, which underscores the importance of isogenic controls when interpreting AD-relevant phenotypes. Going forward, the key translational question is whether improving lysosomal function in microglia can correct both impaired Aβ handling and inflammasome vulnerability, potentially creating new upstream opportunities for therapeutic intervention.

    View all comments by Adamantios Mamais

  2. This work by Terzioglu and Young-Pearse is a tour de force in terms of defining a molecular mechanism through which INPP5D/SHIP1 regulates both inflammasome activation and phagocytosis in microglia. They provide a methodical and deep dissection on how SHIP1 regulates endo-lysosomal function, and how this mechanistically leads to NLRP3 inflammasome activation and the secretion of neurotoxic proinflammatory cytokines such as IL-1 and IL-18. By revealing a critical role for cathepsin B leakage into the cytosol as the key trigger that incites NLRP3 inflammasome activation, the authors have identified a novel molecular player to target in AD. 

    Importantly, cathepsin B inhibitors such as CA-074-Me could offer a more precise strategy to abrogate the key inducers of pathogenic inflammasome-dependent cytokine production while retaining potential beneficial functions that the NLRP3 inflammasome is known to have in mounting of protective anti-pathogen responses.  

    View all comments by John Lukens

  3. INPP5D was identified as an AD risk gene in 2021 by Wightman et al. and Tsai et al. This was followed by target-validation experiments studying the protein SHIP1 in induced microglia (iMGs) and genetically manipulated mice from several groups (Castranio et al., 2022; Jesudason et al., 2023; Zajac et al., 2023). Like several neuroinflammatory risk genes for AD, the effects of INPP5D knockout or overexpression in mouse models varied with the model and disease stage when the SHIP1 levels were altered (Gandy and Ehrlich, 2023).

    By virtue of its unusual catalytic activity, SHIP1 sits at an intersection of a range of phenotypes associated with signal transduction via protein phosphorylation or Ca2+ on one hand and fine control of endosome and lysosome biogenesis and positioning on the other. The phospholipid dephosphorylation reaction prevents receptor activation and mitigates signal transduction through the PI3K/mTOR pathway. SHIP1 inhibits phagocytic signal transduction by TREM2 and Tyrosine kinase Binding Protein TYROBP, aka DAP12. Constitutive deletion or pharmacologic inhibition of SHIP1 increases hematopoietic cell proliferation and phagocytosis of various substances, including zymosan in SHIP1 knockout macrophages and Aβ in inhibited microglia.

    In 2024, Chou et al. reported that one important subcellular action of SHIP1 involved control of NLRP3 inflammasome activation. Both SHIP1 and NLRP3 are considered potential therapeutic targets for treatment, delay or prevention of AD. Now, Terzioglu and colleagues report that lysosomal leakage plays a role in connecting SHIP1 to NLRP3 activation. Lysosomal leakage during neurodegeneration is known to involve transfer of intralumenal lysosomal enzymes such as cathepsin B (Hook et al., 2025). Genetic or pharmacological manipulation of cathepsin B attenuates neurodegeneration in mouse models of AD (Kindy et al., 2012; Hook et al., 2023).

    Repair of leaky lysosomes is coordinated via the phosphoinositide pathway, and efficient repair is required to sustain cell viability (Radulovic et al., 2025). This pathway also coordinates the balance between homeostatic nutrient utilization and mTOR activation versus DAM-associated phagocytic activity. What is not yet clear are the specific SHIP1 substrates and/or catalytic products that maintain lysosomal integrity and which partners are required for execution of this step. In a recent review, Ebner et al. identify some of the known modulators of lysosomal membrane repair, including LMP (lightning bolts in image below) and provide this schematic of how PI(4)P, PI(3P)P, ATG2, VPS13C, BLTP3, OSBP, ORP8/9/11, and ESCRT proteins converge on LMP.

    Now, Terzioglu et al. have used proximity ligation to demonstrate that SHIP1 interacts directly with CD2AP and CapZ proteins. To investigate this further, they measured glycoprotein nonmetastatic melanoma protein B secretion in iMGs, since GPNMB is secreted in response to lysosomal stress and promotes reacidification of lysosomes. Acute SHIP1 inhibition with SHIP1-specific inhibitor 3AC41 dose-dependently reduced LMP as measured by LysoTracker while not affecting cell viability. While these data support a role for SHIP1 activity in regulating lysosome homeostasis, the SHIP1 partners and/or SHIP1 substrates or reaction products that underlie this effect remain to be elucidated. In other words, one of the next steps will be connecting specific SHIP1 partners and/or substrates and/or reaction products with LMP so that the SHIP1 reaction and its topology can be specified in the cartoon above from the Ebner et al.’s review .

    Where along the lysosomal limiting membrane is SHIP1 acting and exactly which other molecules are involved? Identifying these molecules will not only clarify the role of SHIP1 but is also likely to point to novel therapies that might prevent both LMP-related SHIP1 activation of NLRP3 as well as LMP-mediated leakage of cathepsin B into the cytosol and triggering of neurodegeneration.

    References:

    Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, Rongve A, Børte S, Winsvold BS, Drange OK, Martinsen AE, Skogholt AH, Willer C, Bråthen G, Bosnes I, Nielsen JB, Fritsche LG, Thomas LF, Pedersen LM, Gabrielsen ME, Johnsen MB, Meisingset TW, Zhou W, Proitsi P, Hodges A, Dobson R, Velayudhan L, Heilbron K, Auton A, 23andMe Research Team, Sealock JM, Davis LK, Pedersen NL, Reynolds CA, Karlsson IK, Magnusson S, Stefansson H, Thordardottir S, Jonsson PV, Snaedal J, Zettergren A, Skoog I, Kern S, Waern M, Zetterberg H, Blennow K, Stordal E, Hveem K, Zwart JA, Athanasiu L, Selnes P, Saltvedt I, Sando SB, Ulstein I, Djurovic S, Fladby T, Aarsland D, Selbæk G, Ripke S, Stefansson K, Andreassen OA, Posthuma D. Author Correction: A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease. Nat Genet. 2021 Dec;53(12):1722. PubMed.

    Tsai AP, Lin PB, Dong C, Moutinho M, Casali BT, Liu Y, Lamb BT, Landreth GE, Oblak AL, Nho K. INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia. Neurobiol Dis. 2021 Jun;153:105303. Epub 2021 Feb 22 PubMed.

    Castranio EL, Hasel P, Haure-Mirande JV, Ramirez Jimenez AV, Hamilton BW, Kim RD, Glabe CG, Wang M, Zhang B, Gandy S, Liddelow SA, Ehrlich ME. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease. Alzheimers Dement. 2022 Nov 30; PubMed.

    Jesudason CD, Mason ER, Chu S, Oblak AL, Javens-Wolfe J, Moussaif M, Durst G, Hipskind P, Beck DE, Dong J, Amarasinghe O, Zhang ZY, Hamdani AK, Singhal K, Mesecar AD, Souza S, Jacobson M, Salvo JD, Soni DM, Kandasamy M, Masters AR, Quinney SK, Doolen S, Huhe H, Rizzo SJ, Lamb BT, Palkowitz AD, Richardson TI. SHIP1 therapeutic target enablement: Identification and evaluation of inhibitors for the treatment of late-onset Alzheimer's disease. Alzheimers Dement (N Y). 2023;9(4):e12429. Epub 2023 Nov 17 PubMed.

    Zajac DJ, Simpson J, Zhang E, Parikh I, Estus S. Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer's Disease Neuropathology and Genetics. Genes (Basel). 2023 Mar 21;14(3) PubMed.

    Gandy S, Ehrlich ME. Correction: miR155, TREM2, INPP5D: Disease stage and cell-type are essential considerations when targeting clinical interventions based on mouse models of Alzheimer's amyloidopathy. J Neuroinflammation. 2023 Nov 30;20(1):288. PubMed.

    Chou V, Pearse RV 2nd, Aylward AJ, Ashour N, Taga M, Terzioglu G, Fujita M, Fancher SB, Sigalov A, Benoit CR, Lee H, Lam M, Seyfried NT, Bennett DA, De Jager PL, Menon V, Young-Pearse TL. INPP5D regulates inflammasome activation in human microglia. Nat Commun. 2023 Nov 29;14(1):7552. PubMed.

    Hook V, Podvin S, Yoon MC, Phan VV, Florio J, Spencer B, Mosier C, Cheng A, Ahuett S, Almaliti J, Gerwick WH, Rissman RA, O'Donoghue AJ. Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel Drug Targeting Strategy for Traumatic Brain Injury and Alzheimer's Disease. ACS Chem Biol. 2025 Aug 15;20(8):1841-1848. Epub 2025 Jul 23 PubMed.

    Kindy MS, Yu J, Zhu H, El-Amouri SS, Hook V, Hook GR. Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence. J Alzheimers Dis. 2012;29(4):827-40. PubMed.

    Hook V, Podvin S, Yoon MC, Phan VV, Florio J, Spencer B, Mosier C, Cheng A, Ahuett S, Almaliti J, Gerwick WH, Rissman RA, O'Donoghue AJ. Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel Drug Targeting Strategy for Traumatic Brain Injury and Alzheimer's Disease. ACS Chem Biol. 2025 Aug 15;20(8):1841-1848. Epub 2025 Jul 23 PubMed.

    Radulovic M, Yang C, Stenmark H. Lysosomal membrane homeostasis and its importance in physiology and disease. Nat Rev Mol Cell Biol. 2025 Aug 4; Epub 2025 Aug 4 PubMed.

    Ebner M, Fröhlich F, Haucke V. Mechanisms and functions of lysosomal lipid homeostasis. Cell Chem Biol. 2025 Mar 20;32(3):392-407. Epub 2025 Mar 6 PubMed.

    View all comments by Michelle Ehrlich View all comments by Sam Gandy

  4. This fascinating study once again highlights endolysosomal damage as a nexus for Alzheimer’s. For me, one of the most interesting aspects is the biological convergence of so many risk loci linked to AD and to PD, with CTSB being one of a handful of genes implicated by GWAS in both disorders. To CTSB you can add RAB32 (recently identified as a locus for Parkinson’s), TMEM175, and GPNMB (both from Parkinson’s GWAS).

    Understanding how and why these contribute to one disease or the other (or both) is going to be critical, and this study provides important an mechanistic insight into this area.

    View all comments by Patrick Lewis

  5. This study represents a significant advance in understanding how INPP5D/SHIP1, an Alzheimer disease risk gene, regulates microglial function. Building on their earlier observation that reduced INPP5D activates the NLRP3 inflammasome in iPSC-derived microglia (Chou et al., 2023), the authors now demonstrate that SHIP1 interacts with CapZ family proteins and SHIP2, localizes in part to endolysosomes, and that reducing INPP5D impairs endosome maturation and lysosomal function.

    The study makes several notable contributions. First, identifying SHIP1’s interaction with the CapZ complex and the formation of SHIP1-SHIP2 complexes reveals functions for SHIP1 beyond its canonical role as a negative regulator of PI3K signaling. Second, comprehensive cell-state analysis including CITE-Seq shows that INPP5D reduction markedly attenuates transcriptional responses to LPS while shifting microglia toward a DAM-like phagocytic state, indicating that microglial functional states are more complex than a simple "activation" paradigm. Third, the authors show intracellular accumulation of Aβ and lipid droplets together with TREM2-dependent increases in engulfment of synaptic material, which are highly relevant to Alzheimer disease pathology.

    Regarding the proposed mechanism of inflammasome activation via cathepsin B leakage from lysosomes into the cytosol, careful consideration is warranted. While the authors demonstrate that SHIP1 inhibitor-induced inflammasome activation is rescued by a cathepsin inhibitor, this indicates that cathepsin activity is required upstream but does not directly prove cytosolic leakage of cathepsin B. The observed reduction in cathepsin B-positive puncta despite elevated overall protein levels and enzymatic activity is suggestive of lysosomal membrane permeabilization, but direct detection of cytosolic cathepsin B and its mechanistic link to endolysosomal dysfunction would further strengthen this conclusion in future work.

    A remaining question is how these human iPSC-microglia phenotypes relate to outcomes reported in mouse models. Earlier reports, including from our group, have described protective effects of INPP5D deficiency on dystrophic neurites surrounding amyloid plaques in vivo (Lin et al., 2023; Samuels et al., 2023; Iguchi et al., 2023; Yin et al., 2023). At first glance, such protection might seem at odds with inflammasome activation observed here. However, the present study also reports markedly reduced LPS responsiveness and a contraction of inflammatory signaling clusters alongside expansion of a DAM-like state. These observations raise the possibility that dampened responsiveness to classical inflammatory stimuli and decreased inflammatory signaling clusters underlie the protective phenotypes observed in mouse models. Defining which components of INPP5D reduction are most relevant to in vivo pathological outcomes will be essential for SHIP1-targeted therapeutic strategies, including whether interventions should enhance or suppress SHIP1 activity in specific disease contexts.

    References:

    Chou V, Pearse RV 2nd, Aylward AJ, Ashour N, Taga M, Terzioglu G, Fujita M, Fancher SB, Sigalov A, Benoit CR, Lee H, Lam M, Seyfried NT, Bennett DA, De Jager PL, Menon V, Young-Pearse TL. INPP5D regulates inflammasome activation in human microglia. Nat Commun. 2023 Nov 29;14(1):7552. PubMed.

    Lin PB, Tsai AP, Soni D, Lee-Gosselin A, Moutinho M, Puntambekar SS, Landreth GE, Lamb BT, Oblak AL. INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease. Alzheimers Dement. 2023 Jun;19(6):2528-2537. Epub 2022 Dec 16 PubMed.

    Samuels JD, Moore KA, Ennerfelt HE, Johnson AM, Walsh AE, Price RJ, Lukens JR. The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology. Alzheimers Dement. 2023 Apr 15; PubMed.

    Iguchi A, Takatori S, Kimura S, Muneto H, Wang K, Etani H, Ito G, Sato H, Hori Y, Sasaki J, Saito T, Saido TC, Ikezu T, Takai T, Sasaki T, Tomita T. INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model. iScience. 2023 Apr 21;26(4):106375. Epub 2023 Mar 13 PubMed.

    Yin Z, Rosenzweig N, Kleemann KL, Zhang X, Brandão W, Margeta MA, Schroeder C, Sivanathan KN, Silveira S, Gauthier C, Mallah D, Pitts KM, Durao A, Herron S, Shorey H, Cheng Y, Barry JL, Krishnan RK, Wakelin S, Rhee J, Yung A, Aronchik M, Wang C, Jain N, Bao X, Gerrits E, Brouwer N, Deik A, Tenen DG, Ikezu T, Santander NG, McKinsey GL, Baufeld C, Sheppard D, Krasemann S, Nowarski R, Eggen BJ, Clish C, Tanzi RE, Madore C, Arnold TD, Holtzman DM, Butovsky O. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. Nat Immunol. 2023 Nov;24(11):1839-1853. Epub 2023 Sep 25 PubMed.

    View all comments by Taisuke Tomita View all comments by Sho Takatori

  6. This study by Terzioglu et al. is a continuation of what they described before (Chou et al., 2023). In that prior paper, Chou and colleagues identified the AD GWAS hit INPP5D as a key negative regulator of the NLRP3 inflammasome in human microglia, with reduced functional INPP5D in AD being associated with increased inflammasome activity, disrupted autophagy/lysosomal pathways, and altered microglia–neuron crosstalk. They also showed that INPP5D inhibition modulated expression of several AD GWAS genes, including CD33, TMEM106B, CTSH, GRN, PTK2B, and CD2AP, and they proposed candidate links through CLEC7A/Dectin-1, PLA2G7/LysoPC, and lysosome/autophagy perturbations, but left the mechanism open.

    This time, Terzioglu and colleagues take the story further by tackling how INPP5D/SHIP1 deficiency causes NLRP3 inflammasome activation and broader microglial dysfunction. They show that SHIP1 is not restricted to the plasma membrane but localizes to endo-lysosomal compartments (e.g., with CAPZA1/2, CAPZB), that INPP5D-haploinsufficient induced microglia (iMGs) develop early endosome defects, have reduced autophagic flux, and accumulate lipid droplets, and that loss of SHIP1 leads to lysosomal membrane permeabilization, cathepsin B leakage into the cytosol, and NLRP3 inflammasome activation.

    At the level of microglial cell state, they observe loss of an immune-responsive, chemokine-producing CCL2/3/4⁺ CD13⁺ NF-κB-driven cluster and expansion of a DAM-like, hyper-phagocytic, synapse-pruning, Aβ-retaining state, enriched for APOE, TREM2, CD64, and Fcγ receptors, deepening the AD relevance of this pathway. In line with seminal work establishing the NLRP3 inflammasome as a central driver of AD-related neuroinflammation and neurodegeneration (Heneka et al., 2013; Ising et al., 2019; McManus et al., 2025), these findings now position INPP5D/SHIP1 and the endo-lysosomal network as key upstream modulators of this axis, building a mechanistic bridge between INPP5D deficiency and NLRP3 inflammasome activation.

    Taken together with recent endo-lysosomal, GWAS-focused studies, such as that by Kozlova and colleagues on PICALM (Kozlova et al., 2025), this elegant work sharpens the therapeutic angle by firmly linking endo-lysosomal AD GWAS hits to discrete microglial states in Alzheimer’s disease, helping to prioritize targetable nodes within these GWAS-informed networks for future interventions. 

    References:

    Chou V, Pearse RV 2nd, Aylward AJ, Ashour N, Taga M, Terzioglu G, Fujita M, Fancher SB, Sigalov A, Benoit CR, Lee H, Lam M, Seyfried NT, Bennett DA, De Jager PL, Menon V, Young-Pearse TL. INPP5D regulates inflammasome activation in human microglia. Nat Commun. 2023 Nov 29;14(1):7552. PubMed.

    Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.

    Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, Griep A, Santarelli F, Brosseron F, Opitz S, Stunden J, Merten M, Kayed R, Golenbock DT, Blum D, Latz E, Buée L, Heneka MT. NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov;575(7784):669-673. Epub 2019 Nov 20 PubMed.

    McManus RM, Komes MP, Griep A, Santarelli F, Schwartz S, Ramón Perea J, Schlachetzki JC, Bouvier DS, Khalil MA, Lauterbach MA, Heinemann L, Schlüter T, Pour MS, Lovotti M, Stahl R, Duthie F, Rodríguez-Alcázar JF, Schmidt SV, Spitzer J, Noori P, Maillo A, Boettcher A, Herron B, McConville J, Gomez-Cabrero D, Tegnér J, Glass CK, Hiller K, Latz E, Heneka MT. NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression. Immunity. 2025 Feb 11;58(2):326-343.e11. Epub 2025 Feb 3 PubMed.

    Kozlova A, Zhang S, Sudwarts A, Zhang H, Smirnou S, Byeon SK, Thapa C, Sun X, Stephenson K, Zhao X, Jamison B, Ponnusamy M, He X, Schneider JA, Pandey A, Bennett DA, Pang ZP, Sanders AR, Bellen HJ, Thinakaran G, Duan J. PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia. Nature. 2025 Sep 3; Epub 2025 Sep 3 PubMed.

    View all comments by Bora Tastan

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References

News Citations

  1. Alzheimer’s Microglial Risk Gene INPP5D Revs Up Inflammasome
  2. Expunging Microglial Lipid Droplets Boosts Phagocytosis

Paper Citations

  1. Zajac DJ, Simpson J, Zhang E, Parikh I, Estus S. Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer's Disease Neuropathology and Genetics. Genes (Basel). 2023 Mar 21;14(3) PubMed.
  2. Tsai AP, Lin PB, Dong C, Moutinho M, Casali BT, Liu Y, Lamb BT, Landreth GE, Oblak AL, Nho K. INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia. Neurobiol Dis. 2021 Jun;153:105303. Epub 2021 Feb 22 PubMed.
  3. Chou V, Pearse RV 2nd, Aylward AJ, Ashour N, Taga M, Terzioglu G, Fujita M, Fancher SB, Sigalov A, Benoit CR, Lee H, Lam M, Seyfried NT, Bennett DA, De Jager PL, Menon V, Young-Pearse TL. INPP5D regulates inflammasome activation in human microglia. Nat Commun. 2023 Nov 29;14(1):7552. PubMed.
  4. McQuade A, Coburn M, Tu CH, Hasselmann J, Davtyan H, Blurton-Jones M. Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Mol Neurodegener. 2018 Dec 22;13(1):67. PubMed.
  5. Wu X, Miller JA, Lee BT, Wang Y, Ruedl C. Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer's disease mouse model. Sci Adv. 2025 Feb 7;11(6):eadq6038. Epub 2025 Feb 5 PubMed.

Further Reading

Primary Papers

  1. Terzioglu G, Karp ES, Heuer SE, Haage VC, DeJager PL, Young-Pearse TL. INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia. 2025 Oct 27 10.1101/2025.10.27.684632 (version 1) bioRxiv.

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