In a study published in Immunity, a research team led by Prof. YUAN Junying from the Shanghai Institute of Organic Chemistry (SIOC) of the Chinese Academy of Sciences elucidated the regulatory mechanism of late-onset Alzheimer’s disease (LOAD) risk gene INPP5D in microglial RIPK1 activation, and uncovered a new molecular link between neuroinflammation and LOAD with amyotrophic lateral sclerosis (ALS) comorbidity.

INPP5D, a key genetic risk factor for LOAD, is highly expressed in microglia, but its functional mechanism remains unclear. In this study, researchers found that the N-terminal SH2 domain of INPP5D directly bound to the p-Y383 site of RIPK1, a serine/threonine kinase mediating neuroinflammation, to suppress its kinase activation. This process was independent of INPP5D’s phosphatase activity.

Moreover, researchers showed that microglial INPP5D deficiency cell-autonomously activated RIPK1, driving the transcription of diverse proinflammatory mediators including Toll-like receptors, inflammasomes and complement factors and 17 LOAD risk genes such as ApoE and Trem2. In aging mice, myeloid INPP5D deficiency induced RIPK1-dependent dystrophic microglia, neuronal TDP-43 pathology, cortical neuron and motoneuron loss, as well as motor dysfunction in a non-cell-autonomous manner.

Notably, researchers found that RIPK1-regulated gene signatures in INPP5D-deficient murine microglia were highly consistent with lipid-processing and inflammatory microglial subtypes in human AD brains. In human iPSC-derived microglia carrying the AD-associated INPP5D risk allele, RIPK1 inhibition by Nec-1s effectively suppressed the proinflammatory response and downregulated AD risk genes, mirroring the results in mouse models.

Genetic or pharmacological inhibition of RIPK1 reversed the above pathological changes in mice and human microglia, confirming RIPK1 as a downstream effector of INPP5D. This study identifies INPP5D as an intracellular rheostat controlling RIPK1-mediated neuroinflammation, and highlights RIPK1 kinase as a promising therapeutic target for LOAD and AD-ALS comorbidity.