Age-dependent Shift in the de Novo Proteome Accompanies Pathogenesis in an Alzheimer’s Disease Mouse Model

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, however neuropathological changes begin years before memory impairment. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic alterations in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label and enrich newly synthesized proteins, we found that the de novo proteome is disturbed in young APP/PS1 mice prior to symptom onset, affecting the synthesis of multiple components of the synaptic, lysosomal and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout development. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.

Trazodone rescues dysregulated synaptic and mitochondrial nascent translatomes in prion neurodegeneration

“…In K3 mice mice 43 , AHA labelling of the whole brain proteome over 16 hours in 5 months old mice showed, similar to our findings, a large reduction in neuronal protein synthesis rates measured by FUNCAT 43 . Proteomics analysis showed reduced differentially expressed proteins related to OXPHOS complexes, the TCA cycle, microtubules and actin cytoskeleton, synaptic proteins and ribosomal proteins, confirmed in rTg4510 mice, again similar to our findings and to results from hippocampal slices from APP/PS1 mice 44 , examined by AHA labelling over 5 hours combined with SILAC (BONLAC) which again revealed changes in synapses, proteasome, lysosome, OXPHOS and ribosomal proteins 44 . A separate study in APP/PS1 mice, heavy labeled AHA hippocampal proteome showed similar changes 45 .…”

“…Yet the precise nature and identity of these dysregulated proteins has only recently begun to be explored [43][44][45] and is an important focus for an increased understanding of the subcellular mechanisms and processes that lead to neuronal dysfunction and death.…”

“…We hypothesize that this restoration of key metabolic processes in astrocytes aids in the synaptic protection discussed above. Importantly, mitochondrial dysfunction, ultimately leading to a lowering in ATP production, is not exclusive to prion disease but has been described throughout the spectrum of neurodegenerative diseases [76][77][78][79]81,82,86,87 , including Alzheimer's 44,45,76,77,82,86 , Parkinson's 88 , tauopathies 43,87 and ALS 78 .…”

“…More recently and relevant to our study, the de novo translatome has been examined using NCAT in mouse models of frontotemporal dementia (K3 FTD) 43 and APP/PS1 model of Alzheimer's disease 44,45 . In K3 mice mice 43 , AHA labelling of the whole brain proteome over 16 hours in 5 months old mice showed, similar to our findings, a large reduction in neuronal protein synthesis rates measured by FUNCAT 43 .…”

“…Earlier bulk proteomic studies in prion diseased mice showed changes relating to decreased calcium signalling 41 , neuroinflammation and complement activation 42 . Recently, the de novo proteomes in mouse models of tauopathy 43 and the APP/PS1 Alzehimer's model 44,45 (both of which have impaired protein synthesis rates 11,19,35,36 ) was analysed, which describes changes in ribosomal 43,44 and mitochondrial and synaptic proteins during the course of disease in bulk tissue or hippocampal slices [43][44][45] . The response of the nascent proteome to modulation of pathways regulating translation in these models was not examined.…”