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tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice.
Uekawa, Ken; Anfray, Antoine; Ahn, Sung Ji; Casey, Nicole; Seo, James; Zhou, Ping; Iadecola, Costantino; Park, Laibaik.
Afiliación
  • Uekawa K; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
  • Anfray A; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
  • Ahn SJ; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
  • Casey N; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
  • Seo J; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
  • Zhou P; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
  • Iadecola C; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
  • Park L; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
Alzheimers Dement ; 20(7): 4572-4582, 2024 07.
Article en En | MEDLINE | ID: mdl-38899570
ABSTRACT

INTRODUCTION:

Amyloid beta (Aß) 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 Aß accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aß-induced neurovascular and cognitive dysfunction.

METHODS:

Tg2576 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.

RESULTS:

Treatment 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.

DISCUSSION:

These 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 (Aß) 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 Aß. 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 Aß and tPA reconstitution may be of therapeutic value.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratones Transgénicos / Circulación Cerebrovascular / Péptidos beta-Amiloides / Activador de Tejido Plasminógeno / Modelos Animales de Enfermedad Límite: Animals Idioma: En Revista: Alzheimers Dement Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratones Transgénicos / Circulación Cerebrovascular / Péptidos beta-Amiloides / Activador de Tejido Plasminógeno / Modelos Animales de Enfermedad Límite: Animals Idioma: En Revista: Alzheimers Dement Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos