Research ArticleAlzheimer’s Disease

Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellings

See allHide authors and affiliations

Science Translational Medicine  18 Nov 2020:
Vol. 12, Issue 570, eaba1871
DOI: 10.1126/scitranslmed.aba1871

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Unraveling axonal traffic jam

The protease BACE1 participates in Aβ production and has been shown to accumulate in dystrophic neurons and contribute to axonal pathology in patients with Alzheimer’s disease (AD) and in animal models. The mechanisms mediating BACE1 accumulation are unclear. Here, Lomoio et al. showed that the Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) plays a main role in BACE1 localization. Deletion of Gga3 resulted in BACE1 accumulation and axonal swelling that was prevented by BACE inhibition. The authors identified a loss-of-function mutation in GGA3 in patients with AD, and Gga3 deletion worsened AD pathology in a mouse model. The results contribute to elucidate the mechanisms mediating axonal damage in AD.

Abstract

Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer’s disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before β-amyloid (Aβ) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aβ, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.

View Full Text

Stay Connected to Science Translational Medicine