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Loss of GDE2 leads to complex behavioral changes including memory impairment.
Daudelin, Daniel; Westerhaus, Anna; Zhang, Nan; Leyder, Erica; Savonenko, Alena; Sockanathan, Shanthini.
Afiliación
  • Daudelin D; The Solomon Snyder Department of Neuroscience, The Johns Hopkins School of Medicine, PCTB 1004, 725 N. Wolfe Street, Baltimore, MD, 21205, USA.
  • Westerhaus A; The Solomon Snyder Department of Neuroscience, The Johns Hopkins School of Medicine, PCTB 1004, 725 N. Wolfe Street, Baltimore, MD, 21205, USA.
  • Zhang N; The Solomon Snyder Department of Neuroscience, The Johns Hopkins School of Medicine, PCTB 1004, 725 N. Wolfe Street, Baltimore, MD, 21205, USA.
  • Leyder E; Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
  • Savonenko A; Molecular Microbiology and Immunology Graduate Program in Life Sciences, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA.
  • Sockanathan S; Department of Pathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD, 21205, USA. alena.savonenko@nih.gov.
Behav Brain Funct ; 20(1): 7, 2024 Apr 04.
Article en En | MEDLINE | ID: mdl-38575965
ABSTRACT

BACKGROUND:

Alzheimer's disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aß deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized.

RESULTS:

Here, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition.

CONCLUSIONS:

Taken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades Neurodegenerativas / Demencia Frontotemporal / Enfermedad de Alzheimer / Esclerosis Amiotrófica Lateral Límite: Aged / Animals / Female / Humans Idioma: En Revista: Behav Brain Funct Asunto de la revista: CEREBRO / CIENCIAS DO COMPORTAMENTO Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades Neurodegenerativas / Demencia Frontotemporal / Enfermedad de Alzheimer / Esclerosis Amiotrófica Lateral Límite: Aged / Animals / Female / Humans Idioma: En Revista: Behav Brain Funct Asunto de la revista: CEREBRO / CIENCIAS DO COMPORTAMENTO Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos