Non-linear microglial, inflammatory and oligodendrocyte dynamics across stages of Alzheimer's disease

Abstract

Alzheimers disease (AD) is characterized by cognitive decline and neuropathological hallmarks including A{beta} plaques and Tau tangles. Emerging evidence indicates oligodendrocyte (OL) dysfunction and demyelination also contribute to disease progression. Here, we analyzed OL markers and inflammatory gene expression in human hippocampal samples at early and late AD stages. In early AD, we observed OL and myelinating pathways downregulation, alongside microglial and astrocytic activation, as well as upregulated chemokine CCL2 and peripheral immune infiltration markers. In late stages, expression of OL-related genes and myelination pathways increase, with a higher NG2/MBP ratio, coinciding with decreased microglial coverage and peripheral immune markers. These findings indicate that early neuroinflammation may impair OL function, while attenuated immune activity in late AD allows partial OL recovery. This study provides insights into stage-specific inflammatory and myelin-related changes in AD, supporting the relevance of understanding oligodendrocyte dynamics and potential regenerative responses for future therapeutic strategies. HighlightsO_LIEarly AD: heightened microglial activation and peripheral infiltration. C_LIO_LILate AD: reduced microglial presence and oligodendrocyte partial recovery. C_LIO_LINeuroinflammation shifts toward remyelination-supporting conditions. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/645240v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@eb5f3forg.highwire.dtl.DTLVardef@ba239eorg.highwire.dtl.DTLVardef@7897feorg.highwire.dtl.DTLVardef@142a6fd_HPS_FORMAT_FIGEXP M_FIG C_FIG