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1.
Neurobiol Dis ; 177: 105991, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36623608

RESUMEN

Neurogranin (Ng), a post-synaptic protein involved in memory formation, has been investigated as a biomarker in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD) and ageing. CSF Ng levels are elevated in AD relative to healthy controls and correlate with cognition; however, few studies have focused on Ng abundance in the brain. Synapse loss in the brain correlates closely with cognitive decline in AD making synaptic biomarkers potentially important for tracking disease progression, but the links between synaptic protein changes in CSF and brain remain incompletely understood. In the current study, Ng abundance was examined in post-mortem human brain tissue across AD, healthy ageing (HA), and mid-life (ML) cohorts. Ng levels were quantified in three brain regions associated with cognitive change found during ageing and neurodegenerative diseases, namely the middle temporal gyrus, primary visual cortex and the posterior hippocampus using immunohistochemistry. To support immunohistochemical analysis, total homogenate and biochemically enriched synaptic fractions from available temporal gyrus tissues were examined by immunoblot. Finally, we examined whether Ng is associated with lifetime cognitive ageing. Ng levels were significantly reduced in AD relative to HA and ML cases across all regions. Additionally Ng was significantly reduced in HA in comparison to ML in the primary visual cortex. Immunoblotting confirms reduced Ng levels in AD cases supporting immunohistochemical results. Interestingly, there was also a significant reduction of synapse-associated Ng in our group who had lifetime cognitive decline in comparison to the group with lifetime cognitive resilience indicating loss of neurogranin in remaining synapses during ageing is associated with cognitive decline. Our findings indicate that increases in CSF Ng reflect loss of brain neurogranin and support the use of CSF Ng as a biomarker of AD and potentially of cognitive decline in healthy ageing.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/metabolismo , Neurogranina/líquido cefalorraquídeo , Disfunción Cognitiva/metabolismo , Encéfalo/metabolismo , Biomarcadores/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo
2.
Alzheimers Dement ; 19(6): 2560-2574, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36547260

RESUMEN

INTRODUCTION: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. METHODS: We examined post-mortem brain tissue from people in mid-life (n = 15), healthy ageing with either maintained cognition (n = 9) or lifetime cognitive decline (n = 8), and Alzheimer's disease (n = 13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer's brain homogenate. RESULTS: Synaptic pathology increased, and expression of genes involved in synaptic signaling decreased between mid-life, healthy ageing and Alzheimer's. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signaling genes compared to people with cognitive decline. DISCUSSION: Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.


Asunto(s)
Enfermedad de Alzheimer , Envejecimiento Cognitivo , Envejecimiento Saludable , Sinapsis , Cognición , Sinapsis/metabolismo , Sinapsis/patología , Encéfalo/metabolismo , Encéfalo/patología , Análisis de Secuencia de ARN , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neuronas/metabolismo , Neuronas/patología , Transmisión Sináptica , Cambios Post Mortem , Envejecimiento Saludable/metabolismo , Envejecimiento Saludable/patología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Gliosis/patología
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