DOI: 10.1161/str.55.suppl_1.20 ISSN: 0039-2499

Abstract 20: Axonal Neuropathy and Inflammatory Response in Peripheral Nerves of a Murine Cerebral Amyloid Angiopathy Model

Dillan A Patel, Alina Sprenger-Svacina, Martin K Svacina, Michael E Maniskas, Kazim A Sheikh, Gang Zhang, Juneyoung Lee
  • Advanced and Specialized Nursing
  • Cardiology and Cardiovascular Medicine
  • Neurology (clinical)

Introduction: Cerebral amyloid angiopathy (CAA) induces intracerebral hemorrhages, small vessel disease, and cognitive decline in elderly individuals. CAA is also associated with slower walking speed and abnormal gait rhythms compared to healthy controls. Little is known regarding the impact of peripheral nervous system abnormalities on CAA-associated gait disturbance. Furthermore, it is unknown whether peripheral nerves pose extracerebral targets of amyloid-related endoneurial inflammation.

Hypothesis: Gait disturbance in a CAA model is associated with peripheral neuropathy through endoneurial inflammation related to amyloid accumulation.

Methods: Aged (19-24 months) Tg-SwDI mice (CAA mice) of both sexes harboring mutations of human amyloid precursor protein (APP) were used as a CAA model. Age-matched C57BL/6 wild-type (WT) mice were used as controls (n=6-11/grp). Gait disturbance and sensorimotor function were assessed via DigiGait and grip strength testing. Flow cytometry was used to analyze immune cells in the sciatic nerve. Tibial nerve morphometry was performed to assess for neuropathy.

Results: CAA mice had weaker grip strength ( CAA: 97.7 ± 17.6 g, WT 111.5 ± 8.1 g, p=0.039 ) and evidence of neuropathic gait disturbances, reflected by increased paw angles ( CAA: 21.1 ± 4.8°, WT 11.7 ± 3.4°, p=0.0002 ) and reduced paw areas ( CAA: 0.4 ± 0.05 cm 2 , WT 0.5 ± 0.06 cm 2 , p=0.013 ) impacting the ground when walking compared to WT mice. Tibial nerve morphometry showed a reduced number of myelinated nerve fibers ( CAA: 1023 ± 230.1, WT 1318 ± 45.8, p=0.0047 ) suggesting potential axonal degeneration in CAA mice. Flow cytometry showed an increase in the count of macrophage (both M1 and M2 subtypes) lineage cells ( M1 CAA: 102.3 ± 29.2, WT 57.9 ± 36.3, p=0.009 ) as well as M1 macrophage associated pro-inflammatory cytokine TNF-α ( CAA: 99.7 ± 28.3, WT 53.8 ± 12.2, p=0.009 ) in sciatic nerves of CAA mice compared to WT mice.

Conclusions: CAA mice display an enhanced inflammatory response within the endoneurium which may contribute to observed axonal degeneration, ultimately impairing sensorimotor function and gait. Further studies are needed to unravel the mechanistic interplay between amyloid pathology, endoneurial inflammation, and axonal neuropathy in this CAA model.

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