Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer’s Disease

Abstract

Background: Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently. Objective: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg). Methods: After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient. Results: In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice. Conclusion: We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability.

Naturally Occurring Antioxidant Therapy in Alzheimer’s Disease

“…Recently, aducanumab, the only potential disease-modifying therapy, was approved by the FDA through the FDA’s accelerated approval program. Aducanumab is a human monoclonal antibody that significantly reduced the formation and increased the clearance of existing Aβ plaques in mouse models of AD [ 364 , 365 , 366 ]. However, there is controversy regarding whether the drug slows disease progression in humans, as findings from currently available clinical trial data indicate strategies that reduce amyloid levels do not significantly improve cognition [ 367 ].…”

Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer’s Disease

“…Furthermore, a recent proteomics study showed that chronic systemic administration of Aducanumab restored the impaired calcium homeostasis in a mouse model of AD (10-month-old tgAPPPS1-21 mice). Analyzing the proteomic changes in senile plaques and surrounding tissue showed that Aducanumab administration caused an increase in abundance of proteins involved in phagocytosis, metabolism, and neuronal and axonal regeneration, and a decrease in abundance of proteins involved in stress and Aβ toxicity [ 42 ].…”

Chronic stress induces NPD‐like behavior in APPPS1 and WT mice with subtle differences in gene expression

“…Coronal brain sections (20 μm) from APPPS1 mice only were attached to Superfrost Plus glass (VWR, Denmark). To assess the level of plaque pathology, prefrontal cortex, isocortex and hippocampus were stained using Thioflavin‐S as previously described 40 . Images were acquired on a Leica DM5500 B upright microscope equipped with Leica DFC450 camera using 2.5× object lens (Leica, Denmark).…”