Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease

Abstract

We report a highly significant correlation between human Alzheimer’s disease (AD) brain proteome changes and those in CRND8 APP695NL/F transgenic mice. Comparing protein changes observed in the CRND8 mice with co-expression networks derived from human Alzheimer’s disease (AD), reveals both conserved and divergent module changes. Many proteins in the most highly conserved module (M42, matrisome) accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic neuronal processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of Aβ in plaques and in blood vessels; further, recombinant MDK and PTN enhance Aβ aggregation into amyloid structures. Multiple M42 proteins bind to fibrillar Aβ42 and a non-human amyloid fibrilin vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart. Notably, our findings establish that proteomic changes in modules observed in human AD brains define an Aβ amyloid “responsome” that is well conserved from mouse models to humans. Further, distinct amyloid structures appear to serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions, and this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.

Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid

“…These proteins either directly bind to amyloid or are associated with amyloid plaques, highlighting their crucial connection to amyloid deposition in the brain. 23,48 As expected, MAPT was not uniquely altered in AD but showed higher elevation in AD than PSP, reflecting higher burden of tau pathology in frontal cortex in AD cases. The remaining signature of increased proteins in AD was associated with nuclear metabolism (SDC4, SPOCK3, CEP63) Two-color heatmap represents strength of positive (red) or negative (blue) correlation, with p values provided for all correlations with p < 0.05.…”

Proteomic Changes in the Human Cerebrovasculature in Alzheimer’s Disease and Related Tauopathies Linked to Peripheral Biomarkers in Plasma and Cerebrospinal Fluid

“…This protein signature, previously mapped to a bulk Brodmann area 9 “Matrisome” module 29 , has been shown to consistently distinguish AD from other proteinopathies. These proteins either directly bind to amyloid or are associated with amyloid plaques, highlighting their crucial connection to amyloid deposition in the brain 29,33 . As expected, MAPT was not uniquely altered in AD but showed higher elevation in AD than PSP, reflecting higher burden of tau pathology in frontal cortex in AD cases.…”

“…This pattern was evident in both bulk and vascular proteomes. Several members of the matrisome module, including SMOC1, MDK, NTN1 have been previously shown to bind Aβ and co-localize with amyloid plaques in AD brains 29,49 and in a mouse model of AD amyloidosis 31,33 . In the current study, beyond the core proteins that are central to the module’s function, we have identified novel markers-SMOC2, ITM2C, HGF, CHADL, and others- that were not discernible at the bulk level using similar database search algorithms.…”

“…This uncovered several modules associated with endothelial, pericyte, and SMC biology. In particular, ‘Matrisome/Heparin binding’ module enriched with amyloid-associated proteins 33 showed high specificity to AD with multiple module members altered in cases with pronounced vascular pathologies. Finally, by integrating the cerebrovascular network proteome with cerebrospinal fluid (CSF) and plasma proteomes from control and AD patients led to the identification of promising AD biomarkers enriched in the cerebrovasculature in brain.…”

Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology

“…Based on this evidence of concordance of pathological changes across species based on our and recent proteomics studies 73 , despite evident inter-species differences between humans and mice, we focused our analysis to canonical transcriptomic markers (Supplementary Data 4) of different neuronal classes 49 , and identified distinct patterns of change of neuronal proteins with aging and genotype (5xFAD vs WT), as well as biological interaction between aging and genotype. Excitatory neuronal proteins (Camk2a, Slc17a7) showed an age-dependent decrease without an impact of genotype.…”