INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease

Abstract

Introduction Inositol polyphosphate‐5‐phosphatase (INPP5D) is a microglia‐enriched lipid phosphatase in the central nervous system. A non‐coding variant (rs35349669) in INPP5D increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear. Methods We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis. Results Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation. Conclusion These data demonstrate that Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.

Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer’s Disease Neuropathology and Genetics

“…Currently, studies investigating the effects of reduced INPP5D expression on amyloid neuropathology in murine models are reporting inconsistent results [ 5 , 21 , 22 ]. Iguchi et al used an INPP5D haplodeficient TREM2 loss-of-function mouse model and showed that downregulation of INPP5D increased microglial association with amyloid beta plaques and partially restored plaque compaction, compared to control animals with normal INPP5D expression [ 21 ].…”

“…Similar to Iguchi et al, Castranio et al also demonstrated that INPP5D downregulation increased microglial association with amyloid beta plaques. Lin et al used an INPP5D haplodeficient 5xFAD mouse model and showed that INPP5D downregulation increased amyloid beta plaque compaction, increased microglial motility to and phagocytosis of amyloid beta plaques, and had a positive effect on cognition [ 5 ]. Overall, the studies by Iguchi et al and Lin et al but not Castranio et al indicate protective effects of reduced INPP5D expression in AD murine models.…”

“…Sixty to 80% of Alzheimer’s Disease (AD) risk is linked to genetics [ 1 ]. Genome-wide association studies (GWAS) for AD have identified multiple single nucleotide polymorphisms (SNPs) in genes associated with AD risk, a large subset of which are primarily expressed in microglia: INPP5D , TREM2 , CD33 , PLCG2 , CASS4 , HLA-DRB5-DRB1 , LILRB2 , MS4A4A , ABI3 , SCIMP , and PTK2B [ 2 , 3 , 4 , 5 , 6 ] and reviewed in [ 7 ] and [ 8 ]. In AD, microglia accumulate around amyloid plaques in the brain and phagocytose neuronal debris, taking on a transcriptional signature termed “disease-associated microglia” (DAM) (reviewed in [ 9 , 10 ]).…”

“…In addition to the negative regulation of PI3K action, SHIP1 also inhibits Syk by competing for its binding to phosphorylated DAP12 [ 17 ]. Although the physiological role of SHIP1 in AD is under investigation in murine studies downregulating SHIP1 expression, currently published reports on these mice show inconsistent results [ 5 , 21 , 22 ].…”

Application of spatial transcriptome technologies to neurological diseases

“…Additionally, CST7 was discovered to be a potentially highly specific marker of AD brain plaques thanks to the presence of a plaque-associated differentially expressed genes signature in spatial transcriptomic analysis. In contrast, another study using an INPP5D-haploinsufficient mouse model (Lin et al, 2022) revealed that INPP5D haploinsufficiency altered pathways related to protein digestion, synaptic plasticity, calcium signaling, and cytokine production in plaque-associated microglia, according to spatial transcriptional profiling of amyloid plaque-associated microglia. It is proposed that INPP5D haploinsufficiency slows neuronal dysfunction and cognitive decline by increasing protective responses in microglia, thereby limiting pathological changes in Aβ.…”