Sequence of proteome profiles in preclinical and symptomatic Alzheimer's disease

Abstract

Proteome profile changes in Alzheimer's disease (AD) brains have been reported. However, it is unclear whether they represent a continuous process, or whether there is a sequential involvement of distinct proteins. To address this question, we used mass spectrometry. We analyzed soluble, dispersible, sodium dodecyl sulfate, and formic acid fractions of neocortex homogenates (mainly Brodmann area 17-19) from 18 pathologically diagnosed preclinical AD, 17 symptomatic AD, and 18 cases without signs of neurodegeneration. By doing so, we identified four groups of ADrelated proteins being changed in levels in preclinical and symptomatic AD cases: earlyresponding, late-responding, gradually-changing, and fraction-shifting proteins. Gene ontology analysis of these proteins and all known AD-risk/causative genes identified vesicle endocytosis and the secretory pathway-related processes as an early-involved AD component. In conclusion, our findings suggest that subtle changes involving the secretory pathway and endocytosis precede severe proteome changes in symptomatic AD as part of the preclinical phase of AD. The respective early-responding proteins may also contribute to synaptic vesicle cycle alterations in symptomatic AD.

Age-Dependent Hippocampal Proteomics in the APP/PS1 Alzheimer Mouse Model: A Comparative Analysis with Classical SWATH/DIA and directDIA Approaches

“…SynGOanalysis revealed no enrichment of these proteins towards a specific subsynaptic compartment or biological process. In contrast, a recent proteomics study on the human (pre-clinical) AD cortex revealed changes in proteins related to the secretory pathway and synaptic vesicle endocytosis (e.g., SYT2 and SH3SGL2) [30], supporting the relevance of synaptic homeostasis in AD disease pathology. Proteins related to these pathways were among early responding, late responding and progressively changing protein groups [30].…”

“…In contrast, a recent proteomics study on the human (pre-clinical) AD cortex revealed changes in proteins related to the secretory pathway and synaptic vesicle endocytosis (e.g., SYT2 and SH3SGL2) [30], supporting the relevance of synaptic homeostasis in AD disease pathology. Proteins related to these pathways were among early responding, late responding and progressively changing protein groups [30]. In the APP/PS1 mouse model of AD, stronger changes in synaptic vesicle endocytosis proteins have been observed at 3-moa [4,31], suggesting the APP/PS1 model recapitulates especially early synaptic changes induced by Aβ.…”

Impact of α-synuclein fibrillar strains and ß-amyloid assemblies on the endolysosomal logistics of mouse cortical neurons

“…At early stages, differentially expressed proteins of the “clathrin-coated endocytic vesicle membrane” (GO: 0030669) and the secretory pathway (R-HSA-432720: “Lysosome Vesicle Biogenesis” and R-HSA-432722: “Golgi-Associated Vesicle Biogenesis”) classes were overrepresented. A comparison of the changes in proteome profile between our neuronal model and the results reported by Li et al, 2021 might help to identify druggable targets for increasing the number of cargoes transported.…”

“…Analyses of neuronal immunoprecipitates of α-syn fibrillar assemblies and Aß polymorphs may be useful for identifying the molecular partners interacting directly with these protein assemblies. A recent postmortem proteomics study identified proteins for which abundance changed at different stages of Alzheimer’s disease (Li et al, 2021). At early stages, differentially expressed proteins of the “clathrin-coated endocytic vesicle membrane” (GO: 0030669) and the secretory pathway (R-HSA-432720: “Lysosome Vesicle Biogenesis” and R-HSA-432722: “Golgi-Associated Vesicle Biogenesis”) classes were overrepresented.…”

“…Analyses of neuronal immunoprecipitates of -syn fibrillar assemblies and Aß polymorphs may be useful for identifying the molecular partners interacting directly with these protein assemblies. A recent postmortem proteomics study identified proteins for which abundance changed at different stages of Alzheimer's disease (Li et al, 2021).…”