Impact of stroke on respiratory function and amyloid-β pathology in Tg-2576 mice.

BACKGROUND

Stroke is a well-established risk factor for dementia, and many patients with Alzheimer's disease exhibit mixed neuropathology that includes both ischemic injury and amyloid-β (Aβ) accumulation. Breathing disturbances, such as apnea, have also been linked to cognitive dysfunction and accelerated dementia progression.

OBJECTIVE

We hypothesized that stroke aggravates respiratory dysfunction and cognitive impairment in Tg-2576 mice.

METHODS

Female Tg-2576 mice (13-17 months old) underwent permanent distal middle cerebral artery occlusion (pd-MCAO), with age- and sex-matched wild-type and sham-operated controls. Cognitive performance was assessed using the Barnes maze. Respiratory parameters were quantified by whole-body plethysmography. Immunofluorescence was performed to measure Aβ deposition in hippocampus and cortex, astrocyte reactivity in retrotrapezoid nucleus (RTN) using GFAP, and LYVE1 in deep cervical lymph nodes (dCLNs). Aβ levels in cerebrospinal fluid were also assessed as a readout related to clearance-associated changes.

RESULTS

Compared with wild-type controls, Tg-2576 mice exhibited increased apnea frequency and impaired cognitive performance. Following pd-MCAO, Tg-2576 mice showed a further increase in apnea events and prolonged escape latencies in the Barnes maze. Stroke was also associated with enhanced astrocyte reactivity in the RTN, increased Aβ deposition in the hippocampus and cortex, and reduced Aβ levels in cerebrospinal fluid, along with decreased LYVE1-positive lymphatic area in dCLNs, suggesting compromised glymphatic-lymphatic clearance.

CONCLUSIONS

Collectively, these findings indicate that stroke worsens respiratory dysfunction, impairs Aβ clearance pathways, and accelerates cognitive decline in Tg-2576 mice. Targeting post-stroke respiratory abnormalities may represent a therapeutic avenue to mitigate dementia-related comorbidity after ischemic injury.