Aß Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer's Disease.

We report a highly significant correlation in brain proteome changes between Alzheimers disease (AD) and CRND8 APP695NL/F transgenic mice. However, integrating protein changes observed in the CRND8 mice with co-expression networks derived from human AD, reveals both conserved and divergent module changes. For the most highly conserved module (M42, matrisome) we find many proteins accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of A ß ; in plaques and in CAA; further, recombinant MDK and PTN enhance A ß ; aggregation into amyloid. Multiple M42 proteins, annotated as heparan sulfate binding proteins, bind to fibrillar A ß 42 and a non-human amyloid fibril in vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart and islet amyloid polypeptide (IAPP) amyloid in the pancreas. Our findings establish several critical insights. Proteomic changes in modules observed in human AD brains define an A ß ; amyloid responsome that is well conserved from mouse model to human. Further, distinct amyloid structures may serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions. We hypothesize that 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.

Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure.

Extracellular amyloid-ß (Aß) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer's disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aß plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aß and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aß plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process.

Color diversity judgments in peripheral vision: Evidence against "cost-free" representations.

Is visual perception "rich" or "sparse?" One finding supporting the "rich" hypothesis shows that a specific visual summary representation, color diversity, is represented "cost-free" outside focally-attended regions in dual-task paradigms [1]. Here, we investigated whether this "cost-free" phenomenon for color diversity perception extends to peripheral vision. After replicating previous findings and verifying that color diversity is represented "cost-free" in central vision, we performed two experiments: in our first experiment, we extended the paradigm to peripheral vision and found that in minimally-attended regions of space, color diversity perception was impaired. In a second and final experiment, we added confidence judgments to our task, and found that participants maintained high levels of metacognitive awareness of impaired performance in minimally-attended visual areas in the periphery. These findings provide evidence that color perception may be partially attention-dependent in peripheral vision, and challenge previous views on both sides of the rich vs. sparse debate.