Aims

Amyloid-beta (Aβ) and Tau protein aggregates lead to neuronal loss and cognitive decline in Alzheimer’s Disease (AD) patients. We have previously described a key role for p53 in Aβ-induced neurodegeneration. Recently, glia-induced neuroinflammation has emerged as a key factor in AD pathophysiology and p53 has been postulated as a modulator of the immune response in microglia. Here, we evaluated the possible role of p53 as a regulator of the microglial response to Aβ, which contributes to neurodegeneration.

Methods

Oligomerized Aβ_25-35 (9 nmol) was intracerebroventricularly injected into wild-type (WT) and p53 knockout (p53KO) mice. Some WT animals were treated intraperitoneally with the p53 transcriptional activity inhibitor, pifithrin-alpha (PFT-α; 2 mg/kg). Neuroinflammation and neurodegeneration were assessed up to 5 days after injection by Western blot and immunofluorescence. Mice cognitive status was evaluated using NOR, Y-Maze and Barnes Maze tests.

Results

We found that Aβ_25-35 oligomers caused p53 accumulation, leading to rapid microglial activation. Also, a switch from M1 (proinflammatory/neurotoxic) to M2 (anti-inflammatory/neuroprotective) microglial profile happened in a p53-dependent manner. Moreover, Aβ_25-35 injection also induced reactive astrogliosis. Together, these events led to neurodegeneration and memory impairment, which were prevented by genetic and pharmacological inhibition of p53.

Conclusions

Our results demonstrate a key role of p53 in the Aβ-induced inflammatory response, which may contribute to neurodegeneration and cognitive impairment in AD.

Funded by Instituto de Salud Carlos III (PI18/00265; RD16/0019/0018); FEDER; Junta de Castilla y León (CSI151P20; co-financed with FEDER funds), European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement 686009).