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. The protein it encodes, SHIP1, is involved in phosphoinositide signaling and interacts with microglial phagocytic receptors like TREM2. It is genetically associated with Alzheimer's disease (AD), and its role in microglial function and related signaling pathways is of great significance [1,2,3].

In KO/CKO mouse models, conditional Inpp5d downregulation in the PSAPP mouse increases plaque burden and recruitment of microglia to plaques [1]. Inpp5d haplodeficiency in PS19 Tauopathy mice mitigates hyperphosphorylated tau levels and motor deficits, with transcriptomic analysis showing up-regulation of genes related to immune response and cell migration [4]. In 5xFAD mouse model of amyloidosis, Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities [5]. Also, SHIP-1 deletion in microglia of 5xFAD Inpp5dfl/fl Cx3cr1Ert2Cre mice leads to enhanced recruitment of microglia to Aβ plaques, altered microglial gene expression, and improvements in neuronal health [6].

In conclusion, Inpp5d plays a crucial role in microglial-mediated processes related to AD. Studies using KO/CKO mouse models have revealed its significance in amyloid and tau pathology, as well as in microglial functions such as phagocytosis, plaque clearance, and immune response. These findings highlight its potential as a therapeutic target for AD [1,4,5,6].

References:

1. 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/

2. 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/

3. 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/

4. 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/

5. 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/

6. 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/