tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice

Author:

Uekawa Ken1,Anfray Antoine1,Ahn Sung Ji1,Casey Nicole1,Seo James1,Zhou Ping1,Iadecola Costantino1,Park Laibaik1

Affiliation:

1. Feil Family Brain and Mind Research Institute, Weill Cornell Medicine New York New York USA

Abstract

AbstractINTRODUCTIONAmyloid beta (Aβ) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aβ accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aβ‐induced neurovascular and cognitive dysfunction.METHODSTg2576 mice and wild‐type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later.RESULTSTreatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid.DISCUSSIONThese findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution.Highlights Amyloid beta (Aβ) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aβ. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aβ and tPA reconstitution may be of therapeutic value.

Funder

National Institutes of Health

Leon Levy Foundation

BrightFocus Foundation

Publisher

Wiley

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