Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer's disease‐like pathology

Abstract

Translational research on Alzheimer's disease (AD) has often focused on reducing the high cerebral levels of amyloid-β (Aβ) as a key characteristic of AD pathogenesis. There is, however, a growing body of evidence that synaptic dysfunction may be crucial for the development of the most common (sporadic) form of AD. The applicability of melatonin (mainly produced by the pineal gland) to the treatment of AD is actively evaluated, but usually, such studies are based on animal models of early-onset AD, which is responsible for only ~5% of AD cases. We have shown previously that in OXYS rats (an established model of sporadic AD), accumulation of toxic forms of Aβ in the brain occurs later than does the development of signs of neurodegenerative changes and synaptic failure. In this regard, recently, we uncovered beneficial neuroprotective effects of melatonin (prophylactic dietary supplementation) in OXYS rats. Our aim here was to evaluate, starting at the age of active progression of AD-like pathology in OXYS rats, the effects of long-term oral administration of melatonin on the structure of synapses and on neuronal and glial cells of the hippocampus. Melatonin significantly increased hippocampal synaptic density and the number of excitatory synapses, decreased the number of inhibitory synapses, and upregulated pre- and postsynaptic proteins (synapsin I and PSD-95, respectively). Furthermore, melatonin improved the ultrastructure of neuronal and glial cells and reduced glial density. Based on our past and present results, the repair of neuroplasticity by melatonin is a promising strategy against AD.

An antioxidant specifically targeting mitochondria delays progression of Alzheimer’s disease-like pathology

“…2B) and the endoplasmic reticulum, decreased specific area of lysosomes and vacuoles, and slightly but not significantly decreased the specific area of the Golgi complex (Table S1). These data corroborate previous reports of neuronal loss and neurodegenerative changes in the hippocampus of OXYS rats at this age [31] and indicate that SkQ1 treatment prevented the neuronal loss and progression of neurodegeneration in these rats.…”

“…3E). Further analyses of the ultrastructural state of pyramidal neurons in the hippocampal CA1 region of the rats revealed significant changes (similar to those showed recently [31]) in the structural organization of the nucleus, nucleolus, Golgi complex, endoplasmic reticulum (Fig. 3F) and mitochondria (Fig.…”

“…In line with their hippocampus-dependent cognitive deficits, OXYS rats show a synaptic loss [31], prominent alterations of synaptic functions [33], and significant ultrastructural changes [28] in the hippocampus. Ultrastructural abnormalities in synaptic terminals of OXYS rats in the period of progression of AD-like pathology are characterized by decreased numbers of synaptic vesicles, by signs of their disorganization and destruction, by increased numbers of various vacuoles, and by swelling and disintegration of mitochondria [31].…”

Antioxidants and Dementia Risk: Consideration through a Cerebrovascular Perspective

“…Furthermore, in aged 22-month old wild-type mice with significantly impaired spatial cognition, melatonin improved cognitive performance by reducing cerebral amyloid burden through altered protein-cleaving secretase expression [97]. In addition, some studies showed that melatonin promotes hippocampal neuroplasticity and stimulates the proliferation and differentiation of neural stem cells in vitro and in vivo [98,99,100]. A number of studies have also demonstrated protective effects of melatonin on the BBB.…”

Synchrony and desynchrony in circadian clocks: impacts on learning and memory

“…However, the action of melatonin on cognitive performance may vary between MT 1 and MT 2 signaling as a MT 2 receptor deletion results in impairments in hippocampal long-term memory (Larson et al 2006). In Alzheimer's disease models, melatonin or MT 2 agonists appear to have a therapeutic effect on cognitive performance and hippocampal neuroplasticity (Bahna et al 2014;Ali and Kim 2015;Stefanova et al 2015). While melatonin has the potential to link the circadian system with memory and performance, the actions of melatonin may vary with circadian phase, task specificity, or receptor signaling.…”