Perrier, V. | Search bioRxiv

bioRxiv2026

APPNL-F knock-in Alzheimer's Disease model mice reveal etiological convergence of aging and amyloidosis

Alzheimers disease (AD) is the leading cause of dementia worldwide, with a steadily increasing prevalence. Despite the advent of some plaque-degrading therapies, early intervention strategies are still suboptimal, largely due to an incomplete understanding of how early pathological events of amyloid-{beta} (A{beta}) plaque deposition entail or accompany the neuroinflammatory processes that ensue. The APPNL-F mouse line is a second-generation endogenous-promoter knock-in AD model that represents a valuable tool to dissect disease mechanisms and evaluate therapeutic strategies. However, the early prodromal stage remains poorly characterized. Here we performed in-depth analyses in both homozygous (APPNL-F/NL-F) and heterozygous (APPNL-F/WT) mice at 3, 6, 9 and 12 months of age. Among a battery of behavioural tests, the first phenotype was observed at 9 months with defects in spatial memory. Using hypersensitive MSD-ELISA technology assays we quantified distinct A{beta} species and found that A{beta}42 oligomers, protofibrils, and fibrillar aggregates were detectable as early as 6 months of age in homozygous APPNL-F/NL-F mice. By 9 months, their A{beta}42 levels increased markedly and overt A{beta} plaques were detected, histologically associated with recruited glial cells. Targeted RT-qPCR analysis of neuroinflammation-related genes in the cortex also identified 9 months as a molecular tipping point in these middle aged APPNL-F mice. To characterize the etiological signal transduction at the cellular level, we isolated microglia, the brain resident immune cells, whose contribution to AD pathogenesis is now well established. Sequencing around 5,000 individual cells from both 12-month-old APPNL-F/NL-F and APPWT/WT CD11b+ myeloid cells revealed that the buildup of amyloidosis was associated with an accelerated shift of microglia from a homeostatic toward a senescent-like state. Together, these findings highlight the 6-12 month period of the APPNL-F/NL-F model as a powerful system to study the interdependence between microglial senescence and amyloidosis in driving AD progression.

neuroscience↗

bioRxiv2024

Chronic potentiation of metabotropic glutamate receptor 2 with a nanobody accelerates amyloidogenesis in Alzheimer's disease.

Immunotherapy of Alzheimers disease (AD) is a promising approach to reduce the accumulation of amyloid-beta (A{beta}), a critical event in the onset of the disease. Targeting the group II metabotropic glutamate receptors, mGlu2 and mGlu3, could be important in controlling A{beta} production, although their respective contribution remains unclear due to the lack of selective tools. Here, we show that enhancing mGlu2 receptor activity increases A{beta}1-42 peptide production whereas activation of mGlu3 has no effect. We show that such a difference likely results from the direct interaction of APP with mGlu3, but not with mGlu2 receptors, that prevents APP amyloidogenic cleavage and A{beta}1-42 peptides production. We then show that chronic treatments of the AD model 5xFAD mice with a brain-penetrating mGlu2-potentiating nanobody accelerated amyloid aggregation and exacerbated memory deficits, but had no effect in control mice. Our results confirm that a selective mGluR2 activation exacerbates AD disease development, suggesting that therapeutic benefices could be obtained with blockers of this receptor. Our study also provides the proof-of-concept that chronic administration of nanobodies targeting neuroreceptors can be envisioned to treat brain diseases.

neuroscience↗