Early Alzheimer's disease pathology in human cortex involves transient cell states.

Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

ZiBu PiYin Recipe Regulates Central and Peripheral Aß Metabolism and Improves Diabetes-associated Cognitive Decline in ZDF Rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cognitive impairment caused by central neuropathy in type 2 diabetes mellitus (T2DM), namely diabetes-associated cognitive decline (DACD), is one of the common complications in patients with T2DM. Studies have shown that brain ß-amyloid (Aß) deposition is a typical pathological change in patients with DACD, and that there is a close relationship between intestinal microorganisms and cognitive impairment. However, the specific mechanism(s) of alteration in Aß metabolism in DACD, and of the correlation between Aß metabolism and intestinal microorganisms remain unknown. AIM OF THE STUDY: Revealing the mechanism of ZBPYR regulating Aß metabolism and providing theoretical basis for clinical evaluation and diagnosis of DACD. MATERIALS AND METHODS: We characterized Aß metabolism in the central and peripheral tissues of Zucker diabetic fatty (ZDF) rats with DACD, and then explored the preventive and therapeutic effects of ZiBu PiYin Recipe (ZBPYR). Specifically, we assessed these animals for the formation, transport, and clearance of Aß; the morphological structure of the blood-brain barrier (BBB); and the potential correlation between Aß metabolism and intestinal microorganisms. RESULTS: ZBPYR provided improvements in the structure of the BBB, attenuation of Aß deposition in the central and peripheral tissues, and a delay in the development of DACD by improving the expression of Aß production, transport, and clearance related protein in ZDF rats. In addition, ZBPYR improved the diversity and composition of intestinal microorganisms, decreased the abundance of Coprococcus, a bacterium closely related to Aß production, and up regulate the abundance of Streptococcus, a bacterium closely related to Aß clearance. CONCLUSION: The mechanism of ZBPYR ability to ameliorate DACD may be closely related to changes in the intestinal microbiome.