No evidence of major integrative brain clearance impairment in an Alzheimer´s disease model of transgenic APPswe/PS1dE9 mice

Abstract

Brain clearance pathways via the interstitial fluid and cerebrospinal fluid are essential for maintaining homeostasis and removing metabolic waste. Disruptions in these processes are linked to neurodegenerative diseases, particularly Alzheimer’s Disease (AD), where an imbalance between amyloid β (Aβ) production and clearance leads to cerebral amyloidosis. Although AD research continues to rely heavily on murine models, including APPswe/PS1dE9 mice, it remains unclear to what extent these models replicate the deficits in brain clearance observed in human AD. We examined AD pathology in transgenic APPswe/PS1dE9 (tg) mice and wildtype (wt) littermates at six, nine and twelve months using immunohistochemistry for Aβ plaques (6E10+) and activated microglia (Iba1+). To assess integrative parameters contributing to brain clearance, we applied two complementary approaches. First, we performed daytime-dependent intrahippocampal injections of a fluorescent tracer in six-month-old tg and wt mice, followed by histological analysis of tracer dispersion 1 h and 3 h after injection. Second, we present a novel, longitudinal and non-invasive approach utilizing washout kinetics of intravenously administered gadolinium-based contrast agents (GBCA) as an integrative proxy to assess brain clearance dynamics. In this novel approach DOTAREM® was administered intravenously and imaging was done with anesthetized tg and wt mice at nine and twelve months of age. Integrity of the blood-brain-barrier was further evaluated via western blot analysis of occludin protein expression. Despite tg mice displayed characteristic AD-like phenotype, with significant, age-dependent Aβ plaque deposition and neuroinflammation no significant differences in the integrative GBCA washout kinetics were detected between wt and tg mice, suggesting that no major deficits in the combined clearance pathways are present. However, contrast-agent uptake showed a general age-dependent increase consistent with aging-related changes known from human studies. Our findings indicate that the APPswe/PS1dE9 mouse model does not exhibit evidence of major integrative brain clearance impairment, despite this being a hallmark of sporadic AD in humans. These results suggest limitations of this model for studying clearance-related mechanisms of late-onset AD, which should be acknowledged when planning future studies using this murine model.