Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid ß plaque formation in mice.
Alzheimers Res Ther
; 14(1): 59, 2022 04 26.
Article
en En
| MEDLINE
| ID: mdl-35473943
ABSTRACT
BACKGROUND:
Slowed clearance of amyloid ß (Aß) is believed to underlie the development of Aß plaques that characterize Alzheimer's disease (AD). Aß is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aß clearance, and promotes Aß plaque formation.METHODS:
To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the α-syntrophin (Snta1) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid ß levels.RESULTS:
In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing Aß and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid ß levels.CONCLUSIONS:
These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_alzheimer_other_dementias
/
6_mental_health_behavioral_disorders
Asunto principal:
Acuaporina 4
/
Enfermedad de Alzheimer
/
Sistema Glinfático
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Alzheimers Res Ther
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos