Impaired Short-Term Plasticity in Mossy Fiber Synapses Caused by Mitochondrial Dysfunction of Dentate Granule Cells Is the Earliest Synaptic Deficit in a Mouse Model of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) in the early stages is characterized by memory impairment, which may be attributable to synaptic dysfunction. Oxidative stress, mitochondrial dysfunction, and Ca 2ϩ dysregulation are key factors in the pathogenesis of AD, but the causal relationship between these factors and synaptic dysfunction is not clearly understood. We found that in the hippocampus of an AD mouse model (Tg2576), mitochondrial Ca 2ϩ handling in dentate granule cells was impaired as early as the second postnatal month, and this Ca 2ϩ dysregulation caused an impairment of post-tetanic potentiation in mossy fiber-CA3 synapses. The alteration of cellular Ca 2ϩ clearance in Tg2576 mice is region-specific within hippocampus because in another region, CA1 pyramidal neuron, no significant difference in Ca 2ϩ clearance was detected between wild-type and Tg2576 mice at this early stage. Impairment of mitochondrial Ca 2ϩ uptake was associated with increased mitochondrial reactive oxygen species and depolarization of mitochondrial membrane potential. Mitochondrial dysfunctions in dentate granule cells and impairment of post-tetanic potentiation in mossy fiber-CA3 synapses were fully restored when brain slices obtained from Tg2576 were pretreated with antioxidant, suggesting that mitochondrial oxidative stress initiates other dysfunctions. Reversibility of early dysfunctions by antioxidants at the preclinical stage of AD highlights the importance of early diagnosis and antioxidant therapy to delay or prevent the disease processes.

ER-mitochondria tethering by PDZD8 regulates Ca 2+ dynamics in mammalian neurons

“…Although several studies have suggested that ER stores and mitochondria can influence dendritic Ca 2+ dynamics (37–47), the functional importance of ER-mitochondria contacts is unknown in neurons. PDZD8 was expressed at high levels throughout the developing and adult mouse central nervous system (CNS), including in the neocortex (fig.…”

Anti-inflammatory, anticholinesterase and antioxidant activity of leaf extracts of twelve plants used traditionally to alleviate pain and inflammation in South Africa

“…Besides the neuro-pathologic hallmarks of this disease, oxidative stress has also been recognized as a key factor in its pathogenesis (Lee et al, 2012).…”

Phenolic, flavonoid contents, anticholinesterase and antioxidant evaluation of Iris germanica var; florentina

“…Neurodegenerative disorders such as AD are characterised by reduced cholinergic activity in brain (Nunes-Tavares et al 2012 The enzymes AchE and BchE cause hydrolysis of ACh; therefore, inhibition of these enzymes plays a key role in enhancing cholinergic activity. Besides reduced cholinergic activity, oxidative stress has also been recognised as a key factor in the pathogenesis of AD (Lee et al 2012). Oxidation is an integral process in the cellular metabolism.…”