A novel P75‐neurotrophin receptor antagonist, EVT901, reduces neuroinflammation in the TGFAD344 rat model of Alzheimer’s disease

Abstract

AbstractBackgroundp75‐neurotrophin receptor (p75NTR) plays an important role in cell death in adults and has been associated with age‐related basal forebrain degeneration and in Alzheimer’s disease (AD). A recent study demonstrated the reduced pro‐inflammatory response and improvement of the functional outcome by blocking p75NTR following traumatic brain injury. Here, we aimed to test whether a novel p75NTR antagonist, EVT901, reduces neuroinflammation caused by AD pathology in the TgFAD344 rat model (Tg). We hypothesized that chronic administration of EVT901 will reduce the neuroinflammation caused by amyloidosis and hyperphosphorylated tau in the AD rat model.MethodTwo parallel longitudinal studies were conducted to characterize the progression of amyloidosis and neuroinflammation in TgFAD344 rat models (WT = 15 & Tg = 22) and the effect of EVT901 on neuroinflammation (Tg = 6). In the first study, animals underwent 60‐minute dynamic PET scans using [18F]AZD4694 for amyloid‐beta and [11C]PBR28 for neuroinflammation at 15 and 22 months. During the intervention study, animals received 1 mg/kg of EVT901 for 7 days via tail vein injection at 22 months. These animals also underwent [11C]PBR28 PET one day before and after the intervention. The 1 mg/ml drug was prepared in a 10% PEG‐400/90% saline solution. All PET images were matched to the respective MRI and normalized to the average template. [18F]AZD4694 BPND and [11C]PBR28 BPND were quantified based on the SRTM method using pons and midbrain as a reference region, respectively.ResultThe first study demonstrated a significant increase in [18F]AZD4694 and [11C]PBR28 uptake in both the hippocampus and neocortex in Tg compared to WT at baseline and follow‐up. TgFAD344 rats showed a longitudinal increase in [18F]AZD4694 and [11C]PBR28 binding in similar regions. Our second study demonstrated a significant reduction in [11C]PBR28 binding following the intervention in the hippocampus and parietotemporal cortex.ConclusionThis study demonstrated the amyloid pathology and neuroinflammation in the TgFAD344 rat model is captured by [18F]AZD4694 and [11C]PBR28 in vivo. Furthermore, a novel p75NTR antagonist, EVT901, reduces the neuroinflammation induced by AD pathophysiology. Blocking p75NTR can be considered a novel therapeutic target to reduce neuroinflammation in AD.