Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease

Abstract

BackgroundBesides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer’s disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both.MethodsTo study the impact of microglia on neuritic plaque development, we treated two-month-old 5XFAD mice with a selective colony stimulation factor 1 receptor (CSF1R) inhibitor, PLX3397, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, we analyzed the amount of intraneuronal amyloid and neuritic plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze.ResultsWe found that early long-term PLX3397 administration results in a dramatic reduction of both intraneuronal amyloid as well as neuritic plaque deposition. PLX3397 treated young 5XFAD mice also displayed a significant decrease of soluble fibrillar amyloid oligomers in brain lysates, a depletion of soluble pre-fibrillar oligomers in plasma and an improvement in cognitive function measured by fear conditioning tests.ConclusionsOur findings demonstrate that CSF1R signaling, either directly on neurons or mediated by microglia, is crucial for the accumulation of intraneuronal amyloid and formation of neuritic plaques, suggesting that these two events are serially linked in a causal pathway leading to neurodegeneration and neuritic plaque formation. CSF1R inhibitors represent potential preventative or therapeutic approach that target the very earliest stages of the formation of intraneuronal amyloid and neuritic plaques.

The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration

“…It is currently controversial whether selectively, but uniformly, “turning off” microglia would be expected to have a net benefit for patients with neurodegenerative conditions. There is some evidence that pharmacological colony stimulating factor 1 receptor inhibition, which suppresses microgliosis and even depletes microglia from the brain at high doses, can reduce neuronal death and synaptic dysfunction in AD mouse models . Conversely, microglia clearly participate in the clearance of misfolded proteins and could have mainly adaptive roles in preclinical disease.…”

“…There is some evidence that pharmacological colony stimulating factor 1 receptor inhibition, which suppresses microgliosis and even depletes microglia from the brain at high doses, 21 can reduce neuronal death and synaptic dysfunction in AD mouse models. [75][76][77] Conversely, microglia clearly participate in the clearance of misfolded proteins and could have mainly adaptive roles in preclinical disease. They are also essential to CNS recovery in the aftermath of acute insults such as ischemia 78 and experimental transactive response DNA binding protein 43 kDa proteinopathy.…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…One recent study has indicated that microglial depletion in the CX3CR1 CreER DTR transgenic mouse can lead to enlargement of Aβ plaques and may cause extensive neurite damage (Zhao, Hu, Tsai, Li, & Gan, ). However, early long‐term pharmacologically microglial depletion could finally inhibit plaque deposition and amyloid formation in the 5XFAD mouse model of AD, together with a relatively low level of soluble fibrillar oligomers in the brain (Sosna et al, ). Furthermore, the administration of GW2580 (tyrosine kinase inhibitor) orally can regulate inflammation of both the CNS and peripheral nervous systems in the ALS animal model, attenuating motoneuronal cell death, slowing disease progression and extending life expectancy (Martinez‐Muriana et al, ).…”

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

“…Similarly, a prolonged inhibition of the tyrosine kinase activity of CSF1R blocks microglial proliferation and prevents synaptic degeneration, ameliorating disease progression, in the APP/PS1 model 6 , the 3xTg model 7 and the 5xFAD model 8,9 of AD-like pathology. More recently, our group has validated this disease-modifying mechanism in the P301S mouse of tauopathy, demonstrating that inhibition of CSF1R is effective in repolarising microglia to a homeostatic phenotype, preventing neuronal degeneration 10 .…”