The microglial adaptor protein DAB2 links APOE signaling to dysregulated microglial states in Alzheimer’s Disease (AD)

DAB2 is a RELN- and APOE- endocytic adaptor protein that modulates microglial phagocytic, lipid-handling and complement pathways and shifts microglia away from DAM/LDAM states and towards pro-inflammatory cytokine responsive states relevant to Alzheimer’s Disease.

Introduction: 

RELN-DAB1 modify the risk of familial1 and sporadic2 forms of Alzheimer’s Disease (AD), through their interaction with APOE1. While RELN and APOE4 have opposing effects on amyloid and Tau pathology in mice3, how risk is altered in the human brain is unclear. Schematic shows the hypothesised convergence of RELN and APOE signaling pathways in previously unassessed microglia, based on neuronal and brain endothelial cell4 studies.

 

Methods: 

1) Analysis of human brain microglial transcriptomics

2) In-vivo Reln KO mouse

3) Functional DAB knock-down in human APOE iPSC-microglia

 

Results:

1) RELN-APOE enrichment in human microglia with increasing amyloid pathology in AD. 

Gene set enrichment of RELNcore+DAB1/+DAB2 gene pathways in human microglia in CERAD-high (moderate/frequent neuritic plaques, n=15 donors) vs CERAD-low (none/sparse, n=8 donors) brain regions: EC (high n=15, low n=8), ITG (18/13), PFC (18/10), and V1 (18/13), across pooled APOE genotypes. (APOE carriers: APOE3/E3 n=12, APOE3/E4 n=6, APOE4/E4 n=1). BH*padj<0.05,**padj<0.01,***padj<0.0001. Leading edge genes driving enrichment are shown. Color-bar: NES range of ± 2.0. Panels show APOE3/E3 (left) and APOE4/E4 (right) iPSC-microglia immunostained for DAB2 and actin-labelling phalloidin.

2) Microglial hypotrophied processes & upregulation of CD68 in Reln-deficient mice

3) DAB2 regulates gene networks associated with phagocytic/lysosomal DAM-states in the human AD brain, with deficiency shifting microglia towards pro-inflammatory cytokine-responsive states

Conclusions:

DAB2 silencing: Enhanced pro-inflammatory TNFα/NFΚB, reduced phagocytosis, complement, Aβ clearance & lipid handling.

APOE4 microglia: Increased activation of DAM/LDAM states, extracellular matrix remodeling & reduced cholesterol biosynthesis.

Microglia in human AD brain: Cellular response to cytokine stimulus, Ubiquitin-dependent protein catabolism, PI3K-AKT signalling

 

References:

1 Bracher-Smith et al., 2022

2Lopera et al., 2023

3 Shi et al., 2017 

4 Rossi et al., 2020

5 Haney et al., 2024

6 Sala-Frigerio et al., 2019

7 Mancuso et al., 2024

8 Mathys et al., 2019

9 Wachter et al., 2023, 

AD progression Atlas

10 Kracht et al., 2020 

11 Galatro et al., 2017