Relevance of the COPI complex for Alzheimer’s disease progression in vivo

Abstract

Cellular trafficking and recycling machineries belonging to late secretory compartments have been associated with increased Alzheimer's disease (AD) risk. We have shown that coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-toendoplasmic reticulum retrograde transport, affects amyloid precursor protein subcellular localization, cell-surface expression, as well as its metabolism. We present here a set of experiments demonstrating that, by targeting subunit δ-COP function, the moderation of the COPI-dependent trafficking in vivo leads to a significant decrease in amyloid plaques in the cortex and hippocampus of neurological 17 mice crossed with the 2xTg AD mouse model. Remarkably, an improvement of the memory impairments was also observed. Importantly, human genetic association studies of different AD cohorts led to the identification of 12 SNPs and 24 mutations located in COPI genes linked to an increased AD risk. These findings further demonstrate in vivo the importance of early trafficking steps in AD pathogenesis and open new clinical perspectives.ne of the hallmarks of Alzheimer's disease (AD) is the accumulation of Aβ peptides that aggregate over time to form oligomers and lead ultimately to amyloid plaques. Aβ peptides result from cleavages of the amyloid precursor protein (APP) that occur sequentially (1) and concomitantly with APP trafficking, mainly from the plasma membrane to late endosomes (1, 2). We recently addressed the possible involvement of early trafficking steps and demonstrated that at least one subunit of coat protein complex I (COPI), the main machinery underlying the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER), regulates APP trafficking, controlling its maturation and consequently the production of Aβ peptides (3). These biochemical and cellular findings demonstrate the physiological relevance of the COPI complex in AD. All together, these results indicate that the origin of the increased Aβ production in pathological conditions, when trafficking through the endocytic pathway, might be due to APP maturation-state impairments.Moreover, an in vivo model of impairment in COPI subunit delta (δ-COP), the neurological 17 (Nur17) mouse, was previously developed (4) but not yet studied in the context of AD. This mouse model represents a valuable and unique tool to characterize the relevance of δ-COP in AD etiology. The Nur17 mouse was generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, and positional cloning revealed that it carries a T-to-C missense mutation in δ-COP, leading to partial disruption of intracellular trafficking.Further highlighting the important role of trafficking in regulating Aβ production, in genome-wide association studies (GWASs) essential components of cellular trafficking and recycling involved in the endocytic or retromer pathways (endosometo-Golgi retrieval) have been found to be associated with increased AD risk (5, 6).In our previous study identifying δ-COP as a key regulator of APP biology (3), we demonstra...

Copb2is essential for embryogenesis and hypomorphic mutations cause human microcephaly

“…Notably, a protein associated with neurodegeneration, SCYL1, was shown to interact with COPI subunits and to regulate retrograde Golgi to ER traffic (48). Also of note, COPI function (specifically, the δ -COP subunit) was implicated in the trafficking and metabolism of amyloid precursor protein, suggesting a role in Alzheimer's progression (49).…”

Oligomeric amyloid-β induces early and widespread changes to the proteome in human iPSC-derived neurons

“…COPI function is important to AD pathogenesis, as it regulates APP trafficking, maturation and therefore production of Aβ peptides 72 . Furthermore, SNPs in the COPI subunits gamma-1 and delta have been identified as risk factors for the development of LOAD 73 . Upon COPI depletion, the LOAD related protein TREM2 fails to mature, impairing its cell-surface expression, instead accumulating in the ER-Golgi intermediate compartment 74 .…”

“…Additionally, mice with a missense mutation in COPD develop protein accumulations, ER stress, and neurofibrillary tangles 75 . COPI downregulation leads to excessive accumulation of APP at the Golgi, thereby hindering its maturation into Aβ and cell surface expression, culminating in less Aβ load, reduced Aβ plaque deposition and improved memory 72,73 .…”

Investigation of the intercellular transmission of α-synuclein, amyloid-β and TDP-43

“…COPI function is important in AD pathogenesis, as it regulates APP trafficking, maturation and therefore production of Aβ peptides 247 . Furthermore, SNPs in the COPI subunits gamma-1 and delta have been identified as risk factors for the development of sAD, causing intracellular protein accumulations, ER stress, and promoting deposition of NFTs 248,249 . Conversely, COPI downregulation, as we observed here, may be protective, leading to accumulation of APP at the Golgi and therefore hindering its maturation into Aβ 247,248 .…”