Abstract
Abstract
Cerebrospinal fluid (CSF) flow and the glymphatic system are essential for maintaining brain homeostasis, yet the precise mechanisms driving their profound failure in Alzheimer’s disease (AD) remain largely elusive. Here, we reveal that macroscopic CSF propagates dorsally via the perivascular spaces (PAS) of major ventral arteries—the Circle of Willis (CW), middle cerebral artery (MCA), and olfactory artery (OlfA)—which undergo severe structural degradation in an AD mouse model. High-resolution imaging of the dorsal cortex demonstrates that this structural collapse induces a severe influx blockade; in AD, CSF tracers form massive aggregates within the PAS, physically decoupling the gliovascular interface, while tracers entering the parenchyma are pathologically sequestered by amyloid plaques. Furthermore, we identify an active, cholesterol-mediated clearance mechanism responding to exogenous CSF tracer infiltration. While healthy brains rapidly synthesize and efficiently clear this cholesterol via vascular efflux within 120 minutes, the AD model exhibits blunted cholesterol mobilization and a complete failure of capillary efflux. This terminal bottleneck forces uncleared cholesterol to retrogradely accumulate into pathological aggregates within perivascular pericytes and neuronal somata. Collectively, our findings demonstrate that AD dismantles the entire CSF recirculation loop—from macroscopic ventral entry to terminal microvascular efflux—highlighting pericytic and neuronal lipidosis as fundamental drivers of brain fluid stagnation.