Age-Dependent Neuroplasticity Mechanisms in Alzheimer Tg2576 Mice Following Modulation of Brain Amyloid-β Levels

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.

(-)-Phenserine Attenuates Soman-Induced Neuropathology

“…In accord with recent cellular and animal studies [29], [72], (-)-phenserine mitigated neuronal cell death in surviving animals. Initial gene expression analysis suggests that this neuroprotection is mediated via multiple pathways, including non-cholinergic ones.…”

“…In neuronal cultures, (-)-phenserine and posiphen are reported neuroprotective against glutamate excitotoxicity and oxidative stress and augment the survival of neural stem cells [29]. These actions appear to translate to animal studies, in which increased brain-derived neurotrophic factor (BDNF) levels [29] as well as elevated neurogenesis within the dentate gyrus, increased synaptogenesis and reduced inflammatory markers have been described [29], [79], [72]–[74].…”

Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer’s rat model

“…Neurogenesis plays a vital role in structural neuronal plasticity and network maintenance in the adult brain48, and altered neurogenesis in the adult hippocampus may exacerbate neuronal vulnerability and contribute to cognitive impairments in the course of AD49. Therefore, we compared the expression level of DCX, a marker of newborn neurons, among intranasal insulin- and saline-treated ICV-STZ rats and control rats.…”

What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus

“…As described above, MTL plays a special role in learning and memory, with high demands for life-long plasticity and neurogenesis required for these cognitive functions. Rodent research has shown that Aβ, although usually in extremely high doses, can affect synaptic function by modulation of maturation and plasticity of newborn neurons in hippocampus (Biscaro et al, 2009, Lilja et al, 2013). Thus, the impact of Aβ on the temporal lobes may cause malfunction that cannot be compensated for by mechanisms of neural plasticity elsewhere in the brain.…”