Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

In a pilot study, we introduce fast handheld multispectral optoacoustic tomography (MSOT) of the breast at 28 wavelengths, aiming to identify high-resolution optoacoustic (photoacoustic) patterns of breast cancer and noncancerous breast tissue. We imaged 10 female patients ages 48-81 years with malignant nonspecific breast cancer or invasive lobular carcinoma. Three healthy volunteers ages 31-36 years were also imaged. Fast-MSOT was based on unique single-frame-per-pulse (SFPP) image acquisition employed to improve the accuracy of spectral differentiation over using a small number of wavelengths. Breast tissue was illuminated at the 700-970 nm spectral range over 0.56 seconds total scan time. MSOT data were guided by ultrasonography and X-ray mammography or MRI. The extended spectral range allowed the computation of oxygenated hemoglobin (HBO), deoxygenated hemoglobin (HB), total blood volume (TBV), lipid, and water contributions, allowing first insights into high-resolution breast tissue MSOT cancer patterns. TBV and Hb/HBO images resolved marked differences between cancer and control tissue, manifested as a vessel-rich tumor periphery with highly heterogeneous spatial appearance compared with healthy tissue. We observe significant TBV variations between different tumors and between tumors over healthy tissues. Water and fat lipid layers appear disrupted in cancer versus healthy tissue; however, offer weaker contrast compared with TBV images. In contrast to optical methods, MSOT resolves physiologic cancer features with high resolution and revealed patterns not offered by other radiologic modalities. The new features relate to personalized and precision medicine potential. .

Exposure to low-dose irradiation causes transiently elevated expression of the long ncRNA PARTICLE (gene PARTICLE, promoter of MAT2A-antisense radiation-induced circulating lncRNA). PARTICLE affords both a cytosolic scaffold for the tumor suppressor methionine adenosyltransferase (MAT2A) and a nuclear genetic platform for transcriptional repression. In situ hybridization discloses that PARTICLE and MAT2A associate together following irradiation. Bromouridine tracing and presence in exosomes indicate intercellular transport, and this is supported by ex vivo data from radiotherapy-treated patients. Surface plasmon resonance indicates that PARTICLE forms a DNA-lncRNA triplex upstream of a MAT2A promoter CpG island. We show that PARTICLE represses MAT2A via methylation and demonstrate that the radiation-induced PARTICLE interacts with the transcription-repressive complex proteins G9a and SUZ12 (subunit of PRC2). The interplay of PARTICLE with MAT2A implicates this lncRNA in intercellular communication and as a recruitment platform for gene-silencing machineries through triplex formation in response to irradiation.

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