Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties.However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells.We used a systematic approach guided by single-cell RNA sequencing data to map the organizational structure of the human CD8 + memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically, and transcriptionally distinct stem-like CD8 + memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage.Collectively, these data revealed the existence of parallel differentiation programs in the human CD8 + memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines. 3 MAIN TEXTAntigen recognition by CD8 + naive T cells initiates a program of clonal expansion and effector differentiation that leads to the clearance of infected or malignant cells and the subsequent formation of heterogeneous memory populations that confer durable immunity 1 . These memory populations are thought to be organized in a developmental hierarchy, according to which stem cell memory T (TSCM) cells self-renew and generate long-lived central memory T (TCM) cells and short-lived effector memory T (TEM) cells 2-6 . However, the mechanisms that underlie the enhanced multipotency of TSCM cells relative to TCM cells have not been clearly defined in molecular terms 7 .Memory T cell differentiation can become corrupted under conditions of persistent antigenic stimulation, as observed during chronic viral infections and progressive malignancies, which promote a state of T cell exhaustion, characterized by an orderly loss of effector functions, impaired proliferation, and the upregulation of inhibitory receptors 8 . This dynamic process occurs over a period of weeks after the initial priming event 9,10 and involves the genome-wide accumulation of epigenetic modifications 11,12 . Recent studies have shown that exhausted T (TEX) cell populations are developmentally and functionally heterogeneous, incorporating stem-like progenitors that express T cell factor 1 (TCF1) which give rise to highly differentiated TEX cells that are constitutively dysfunctional and lack TCF1 [13][14][15][16] . Importantly, the therapeutic benefits of immune checkpoint blockade in the context of chronic viral infections and various cancers are thought to operate via these TCF1 + progenitors, which appear susceptible to interventions that specifically target the inhibitory receptor programmed death-1 (PD-1) 13,15,17-20 .

Highlights d Targeted transcriptomics captures immune cell heterogeneity at a low sequencing depth d Antibody panels for sequencing-based protein measurement require validation d Combined protein and transcript measurements highlight T cell heterogeneity d One-SENSE provides an intuitive visualization tool for protein-transcript datasets

No abstract