Inpp5d, also known as Inositol polyphosphate-5-phosphatase D, encodes a dual-specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. It is a myeloid-expressed gene, and its protein product SHIP1 is an important regulator in microglial phagocytosis, immune response, and phosphoinositide signaling. The NLRP3 inflammasome signaling is one of the associated pathways, and Inpp5d is genetically associated with Alzheimer's disease (AD), highlighting its significance in neurodegenerative disease research [1,2,3,4,5,6,7,8,9,10].

In Inpp5d-deficient mouse models, several important findings have emerged. In the PSAPP mouse model, conditional Inpp5d down-regulation increased plaque burden and the recruitment of microglia to plaques [2]. In the 5xFAD mouse model, Inpp5d haplodeficiency enhanced microglial functions by increasing plaque clearance and preserved cognitive abilities [6]. In the PS19 mouse model of Tauopathy, Inpp5d haplodeficiency alleviated tau pathology and motor deficits [7]. Also, loss of Inpp5d in wild-type mice had sex-specific effects on the brain transcriptome, with affected genes enriched for multiple neurodegeneration terms [8]. In 5xFAD Inpp5dfl/fl Cx3cr1Ert2Cre mice, SHIP-1 deletion in microglia led to enhanced microglial recruitment to Aβ plaques, improved neuronal health, and enhanced plaque containment and Aβ engulfment [10].

In conclusion, Inpp5d is a crucial regulator in microglial-mediated processes, especially in the context of AD-related pathology. Mouse models, including KO/CKO models, have been instrumental in revealing its role in plaque formation, microglial function, and cognitive preservation in AD, as well as in tau pathology. These findings offer potential therapeutic strategies targeting Inpp5d for neurodegenerative diseases.

References:

1. Chou, Vicky, Pearse, Richard V, Aylward, Aimee J, Menon, Vilas, Young-Pearse, Tracy L. 2023. INPP5D regulates inflammasome activation in human microglia. In Nature communications, 14, 7552. doi:10.1038/s41467-023-42819-w. https://pubmed.ncbi.nlm.nih.gov/38016942/

2. Castranio, Emilie L, Hasel, Philip, Haure-Mirande, Jean-Vianney, Liddelow, Shane A, Ehrlich, Michelle E. 2022. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 19, 2239-2252. doi:10.1002/alz.12821. https://pubmed.ncbi.nlm.nih.gov/36448627/

3. Terzioglu, Gizem, Young-Pearse, Tracy L. 2023. Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer's disease. In Molecular neurodegeneration, 18, 89. doi:10.1186/s13024-023-00674-9. https://pubmed.ncbi.nlm.nih.gov/38017562/

4. Olufunmilayo, Edward O, Holsinger, R M Damian. 2023. INPP5D/SHIP1: Expression, Regulation and Roles in Alzheimer's Disease Pathophysiology. In Genes, 14, . doi:10.3390/genes14101845. https://pubmed.ncbi.nlm.nih.gov/37895194/

5. Chou, Vicky, Fancher, Seeley B, Pearse, Richard V, Menon, Vilas, Young-Pearse, Tracy L. 2023. INPP5D/SHIP1 regulates inflammasome activation in human microglia. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.02.25.530025. https://pubmed.ncbi.nlm.nih.gov/36865139/

6. Lin, Peter Bor-Chian, Tsai, Andy Po-Yi, Soni, Disha, Lamb, Bruce T, Oblak, Adrian L. 2022. INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 19, 2528-2537. doi:10.1002/alz.12849. https://pubmed.ncbi.nlm.nih.gov/36524682/

7. Soni, Disha M, Lin, Peter Bor-Chian, Lee-Gosselin, Audrey, Chu, Shaoyou, Oblak, Adrian L. 2024. Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 20, 4985-4998. doi:10.1002/alz.14078. https://pubmed.ncbi.nlm.nih.gov/38923171/

8. Dabin, Luke C, Kersey, Holly, Kim, Byungwook, Lamb, Bruce T, Kim, Jungsu. 2024. Loss of Inpp5d has disease-relevant and sex-specific effects on glial transcriptomes. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 20, 5311-5323. doi:10.1002/alz.13901. https://pubmed.ncbi.nlm.nih.gov/38923164/

9. Karch, Celeste M, Goate, Alison M. 2014. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. In Biological psychiatry, 77, 43-51. doi:10.1016/j.biopsych.2014.05.006. https://pubmed.ncbi.nlm.nih.gov/24951455/

10. Samuels, Joshua D, Moore, Katelyn A, Ennerfelt, Hannah E, Price, Richard J, Lukens, John R. 2023. The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 19, 4908-4921. doi:10.1002/alz.13089. https://pubmed.ncbi.nlm.nih.gov/37061460/