Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures

Abstract

Alzheimer’s Disease (AD) is characterized by the accumulation of extracellular amyloid-β (Aβ) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer’s disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aβ. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aβ1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aβ internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

Identification of robust cellular programs using reproducible LDA that impact sex-specific disease progression in different genotypes of a mouse model of AD

“…MicroRNAs (miRNAs) play a role in modulating inflammatory responses in microglia, and their profiles are altered in AD. Notably, the pro-inflammatory miRNA, miR-155 , shows increased expression in the AD brain(23). We found diseaseassociated microglia (DAM) genes such as Trem2, Apoe, Itgax, Clec7a, Axl , and Lpl , alongside typical microglia gene markers such as Tmem119, Olfml3 , and Cd68 with higher weights in sc1 (Fig.…”

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

“…In amyloid mouse models, inhibition of reactive astrogliosis increases Aβ 42 plaque burden (61), whereas shifting microglia to an interferon-responsive state boosts ApoE expression, phagocytosis, containment of plaques, and lessens damage to nearby neurons and synapses (62). However, further shifting of microglia to an overactivated state may increase synaptic engulfment and accelerate the dissemination of tau pathology (63). Mouse models indicate that ApoE controls glial activation, with ApoE4 locking microglia in a homeostatic state with failure to clear neurodegenerative pathology (7, 47).…”

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

“…In amyloid mouse models, inhibition of reactive astrogliosis increases Aβ 42 plaque burden [ 69 ], whereas shifting microglia to an interferon-responsive state boosts ApoE expression, phagocytosis, containment of plaques, and lessens damage to nearby neurons and synapses [ 70 ]. However, further shifting of microglia to an overactivated state may increase synaptic engulfment and accelerate the dissemination of tau pathology [ 71 ]. Mouse models indicate that ApoE controls glial activation, but ApoE4 locks microglia in a homeostatic state, decreasing in phagocytic capacity, and resulting in a failure to clear pathological debris [ 7 , 66 , 72 ].…”