On the causal role of retromer-dependent endosomal recycling in Alzheimer's disease

Abstract

Recent findings ranging from genetics to structural biology, together with studies in human neurons, animal models and patient brains, implicate the retromer-dependent endosomal recycling pathway as both causal and common in Alzheimer’s disease.

Fig. 1 |. Retromer-dependent endosomal recycling and the integrative biology of AD.

Left, endosomal recycling tubules need molecular scaffolds for their formation and stabilization. Polymerized arches of retromer dimers coat the external surface of tubules, and multimers of SORL1 dimers decorate their internal surface. The cytosolic domain of SORL1 interacts with VPS26b at the base of the retromer arches, and functions to stabilize retromer and increase retromer-dependent endosomal recycling. The binding of SORL1 to VPS26b through the tubular membrane may represent the crux of an endosomal tubule scaffold in the service of tubular formation and stabilization, an aspect that is fundamental to retromer’s endosomal recycling function. Middle, reflecting their synaptic biology, neurons heavily depend on the endosomal recycling pathway for their health. Disrupting the pathway by depleting SORL1 or VPS26b triggers and can explain the hallmark cellular pathobiology of AD: for example, glutamate receptor loss and synaptic dysfunction; endosomal swelling; accelerated amyloid-β (Aβ) and tau processing and secretion. In addition, neuronal secretion from the endolysosomal system can provoke neighbouring microglia, which in turn can feed back onto neurons, accelerating the neurodegenerative process. Right, neurons in the trans-entorhinal cortex (indicated in red in the human and mouse brain) have distinct network properties, which may explain why they are found differentially reliant on retromer-dependent endosomal recycling. In the brains of patients with the common late-onset form of AD, VPS26b and SORL1 are found selectively co-deficient in these neurons, a finding phenocopied in Vps26b-knockout mice, which can anatomically explain why synaptic dysfunction and neurodegeneration begins in part in these neurons. TGN, trans-Golgi network.