Abstract
The objective of this study was to investigate the effects of modulating brain amyloid-β (Aβ) levels at different stages of amyloid pathology on synaptic function, inflammatory cell changes and hippocampal neurogenesis, i.e. processes perturbed in Alzheimer’s disease (AD). Young (4- to 6-month-old) and older (15- to 18-month-old) APPSWE transgenic (Tg2576) mice were treated with the AD candidate drug (+)-phenserine for 16 consecutive days. We found significant reductions in insoluble Aβ1-42 levels in the cortices of both young and older transgenic mice, while significant reductions in soluble Aβ1-42 levels and insoluble Aβ1-40 levels were only found in animals aged 15–18 months. Autoradiography binding with the amyloid ligand Pittsburgh Compound B (3H-PIB) revealed a trend for reduced fibrillar Aβ deposition in the brains of older phenserine-treated Tg2576 mice. Phenserine treatment increased cortical synaptophysin levels in younger mice, while decreased interleukin-1β and increased monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels were detected in the cortices of older mice. The reduction in Aβ1-42 levels was associated with an increased number of bromodeoxyuridine-positive proliferating cells in the hippocampi of both young and older Tg2576 mice. To determine whether the increased cell proliferation was accompanied by increased neuronal production, the endogenous early neuronal marker doublecortin (DCX) was examined in the dentate gyrus (DG) using immunohistochemical detection. Although no changes in the total number of DCX+-expressing neurons were detected in the DG in Tg2576 mice at either age following (+)-phenserine treatment, dendritic arborization was increased in differentiating neurons in young Tg2576 mice. Collectively, these findings indicate that reducing Aβ1-42 levels in Tg2576 mice at an early pathological stage affects synaptic function by modulating the maturation and plasticity of newborn neurons in the brain. In contrast, lowering Aβ levels in Tg2576 mice when Aβ plaque pathology is prominent mainly alters the levels of proinflammatory cytokines and chemokines.
Highlights
The accumulation of amyloid-b (Ab) aggregates in the brain is a pathological hallmark of Alzheimer’s disease (AD)
Ab is thought to play a central role in the disease pathogenesis, triggering a cascade of neurodegenerative processes including the activation of inflammatory mediators, altered protein kinase and neurotrophic signaling, oxidative stress, and neuronal and synaptic dysfunction, resulting in the impairment of cognitive functions in AD patients [1], [2], [3], [4], [5]
In vivo positron emission tomography (PET) imaging with amyloid tracers such as Pittsburgh Compound B (11C-PIB), has demonstrated that increased fibrillar Ab deposition in the brain precedes functional changes and cognitive decline in AD patients [6], [7], [8]. 11C-PIB PET imaging has been used to measure changes in brain Ab load in patients with mild AD treated with the potential therapeutical drug (2)-phenserine [9], a non-competitive acetylcholinesterase inhibitor with reported modulatory effects on Ab production [10], [11]
Summary
The accumulation of amyloid-b (Ab) aggregates in the brain is a pathological hallmark of Alzheimer’s disease (AD). We treated transgenic mice overexpressing human APP with the Swedish double mutation (Tg2576), at 4–6 and 15–18 months of age, with (+)-phenserine for 16 days These mice exhibit impaired cognitive functioning and high soluble Ab levels in the brain when very young (,6 months old); insoluble Ab levels are increased and Ab plaques are formed later [30], [17]. We measured a selective decrease in Ab42 levels in the cortices of young Tg2576 mice and demonstrated attenuation of both Ab40 and Ab42 levels after the onset of Ab plaque pathology in the brains of older mice These changes were assessed in relation to levels of brain-derived neurotrophic factor (BDNF), the presynaptic vesicle protein synaptophysin, pro-inflammatory cytokines [interleukin-1b (IL-1b), tumor necrosis factor-alpha (TNF-a) and chemokine monocyte chemoattractant protein-1 (MCP-1)], and hippocampal neurogenesis. Concurrent with the reduction in amyloid levels, phenserine treatment primarily elevated cortical synaptophysin levels and increased the maturation of newborn neurons in the DG of 4- to 6-month-old Tg2576 mice, while significant alterations in IL-1b and MCP-1 were detected in the cortices of 15- to 18-month-old mice
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