Alzheimer's Disease Related Markers, Cellular Toxicity and Behavioral Deficits Induced Six Weeks after Oligomeric Amyloid-β Peptide Injection in Rats

Abstract

Alzheimer’s disease (AD) is a neurodegenerative pathology associated with aging characterized by the presence of senile plaques and neurofibrillary tangles that finally result in synaptic and neuronal loss. The major component of senile plaques is an amyloid-β protein (Aβ). Recently, we characterized the effects of a single intracerebroventricular (icv) injection of Aβ fragment (25–35) oligomers (oAβ25–35) for up to 3 weeks in rats and established a clear parallel with numerous relevant signs of AD. To clarify the long-term effects of oAβ25–35 and its potential role in the pathogenesis of AD, we determined its physiological, behavioral, biochemical and morphological impacts 6 weeks after injection in rats. oAβ25–35 was still present in the brain after 6 weeks. oAβ25–35 injection did not affect general activity and temperature rhythms after 6 weeks, but decreased body weight, induced short- and long-term memory impairments, increased corticosterone plasma levels, brain oxidative (lipid peroxidation), mitochondrial (caspase-9 levels) and reticulum stress (caspase-12 levels), astroglial and microglial activation. It provoked cholinergic neuron loss and decreased brain-derived neurotrophic factor levels. It induced cell loss in the hippocampic CA subdivisions and decreased hippocampic neurogenesis. Moreover, oAβ25–35 injection resulted in increased APP expression, Aβ1–42 generation, and increased Tau phosphorylation. In conclusion, this in vivo study evidenced that the soluble oligomeric forms of short fragments of Aβ, endogenously identified in AD patient brains, not only provoked long-lasting pathological alterations comparable to the human disease, but may also directly contribute to the progressive increase in amyloid load and Tau pathology, involved in the AD physiopathology.

A single intracerebroventricular Aβ25–35 infusion leads to prolonged alterations in arginine metabolism in the rat hippocampus and prefrontal cortex

“…The peptide then diffused gradually from the ventricles and/or the walls of blood vessels to various brain regions, including the hippocampus and frontal cortex. Zussy et al (2013) further reported that the tagged peptide was visible in the brain even at 6 weeks after injection, where there were activated glial cells, provoked cholinergic neuron loss, decreased brain-derived neurotrophic factor levels, and increased APP expression, Ab 1-42 generation and Tau phosphorylation. Moreover, the aggregated peptide led to short-and long-term memory deficits, and induced cell loss in the CA sub-regions of the hippocampus and impaired neurogenesis in the DG at this time point.…”

“…administration (Butterfield et al, 2002;Klementiev et al, 2007;Bergin and Liu, 2010;Gulyaeva and Stepanichev, 2010;Millucci et al, 2010;Zussy et al, 2011Zussy et al, , 2013. Using pre-aggregated Ab 25-35 tagged with a fluorescent dye, Zussy et al (2011) demonstrated that the peptide rapidly penetrated through the ependymal barrier and the surrounding structures, and reached the brain vasculature following the i.c.v.…”

“…Previous research in rodents has shown that a single intracerebroventricular (i.c.v.) infusion/injection of pre-aggregated Ab 25-35 impairs learning and memory through multiple mechanisms, such as activating glial cells, altering cerebrovascular endothelial function and synaptic plasticity, and enhancing oxidative stress, and neuronal apoptosis and death (for reviews see Klementiev et al, 2007;Gulyaeva and Stepanichev, 2010;Millucci et al, 2010;Zussy et al, 2011Zussy et al, , 2013.…”

Intrahippocampal Pathways Involved in Learning/Memory Mechanisms are Affected by Intracerebral Infusions of Amyloid-β25-35 Peptide and Hydrated Fullerene C60 in Rats

“…Disturbances in behavioral, physiological, biochemical and morphological characteristics in rats were observed even six weeks after injection of Aβ25-35 into cerebral ventricles [16] while its toxicity has been shown to be eliminated by С60HyFn pretreatment [17]. Peculiarities of cortical-hippocampal nets involvement in the long-term effects of enhanced Aβ level in the brain and in their treatment with С60HyFn are the main targets in this study.…”

Role of Stress, Immune System and Well-being in Patients with Alzheimer's Disease

“…Regarding anxiety, it has been demonstrated, by using animal models, that elevated cortisol in AD subjects prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD, and that an intracerebroventricular injection of amyloid-β peptide in rats induces memory impairment with alteration of anxiety responses [18].…”