Article

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U710, Montpellier, France.
American Journal Of Pathology (Impact Factor: 4.59). 07/2011; 179(1):315-34. DOI: 10.1016/j.ajpath.2011.03.021
Source: PubMed

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25-35 (Aβ(25-35)) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled Aβ(25-35) peptide was used as negative control. The aggregated forms of Aβ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of Aβ(25-35) decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, Aβ(25-35), the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular Aβ(25-35) injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD.

    • "We then analyzed their vulnerability to A toxicity by injecting into the mouse lateral ventricle an oligomeric preparation of the A 25–35 fragment of the amyloid protein. A 25–35 rapidly induces, in mice or rats, an AD-like pathology with oxidative stress, neuroinflammation, cellular stress, apoptosis, cholinergic and glutamatergic cell loss in the hippocampus or cortex, and learning and memory impairments [27] [28] [29] [30] [31] [32] [33]. Animals were retested in the water-maze and the hippocampal content in ACh and lipid peroxidation levels, an index of oxidative stress, were analyzed. "
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    ABSTRACT: Butyrylcholinesterase (BChE) is an important enzyme for detoxication and metabolism of ester compounds. It also hydrolyzes the neurotransmitter acetylcholine (ACh) in pathological conditions and may play a role in Alzheimer's disease (AD). We here compared the learning ability and vulnerability to Aβ toxicity in male and female BChE knockout (KO) mice and their 129Sv wild-type (Wt) controls. Animals tested for place learning in the water-maze showed increased acquisition slopes and presence in the training quadrant during the probe test. An increased passive avoidance response was also observed for males. BChE KO mice therefore showed enhanced learning ability in spatial and non-spatial memory tests. Intracerebroventricular (ICV) injection of increasing doses of amyloid-β[25-35] (Aβ25-35) peptide oligomers resulted, in Wt mice, in learning and memory deficits, oxidative stress and decrease in ACh hippocampal content. In BChE KO mice, the Aβ25-35-induced deficit in place learning was attenuated in males and blocked in females. No change in lipid peroxidation or ACh levels was observed after Aβ25-35 treatment in male or female BChE KO mice. These data showed that the genetic invalidation of BChE in mice augmented learning capacities and lowered the vulnerability to Aβ toxicity. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Aug 2015 · Behavioural brain research
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    • "In addition, Aí µí»½ induced elevation of reactive oxygen species (ROS) levels in neurons resulting in protein oxidation, lipid peroxidation, ROS formation, and cellular dysfunction, leading to calcium ion accumulation and subsequent neuronal death [8] [9] [10]. Furthermore, Aí µí»½ causes damage to mitochondrial membranes and hence increases the amount of intracellular H 2 O 2 , thus affecting the genes downstream by interacting with numerous receptors and damaging neurons, ultimately accelerating cell death and hippocampus alteration [11] [12] [13]. The hippocampus is a relevant structure that is highly involved in cognition and psychological function and there is evidence that this structure is rapidly and extremely affected by an injection of the Aí µí»½ fragment (Aí µí»½25–35) in rat [14]. "
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder and most common form of dementia that leads to memory impairment. In the present study we have examined the protective effects of Borago officinalis (borage) extract on Amyloid β (A β )-Induced memory impairment. Wistar male rats received intrahippocampal (IHP) injection of the A β (25-35) and borage extract throughout gestation (100 mg/kg). Learning and memory functions in the rats were examined by the passive avoidance and the Morris water maze (MWM) tasks. Finally, the antioxidant capacity of hippocampus was measured using ferric ion reducing antioxidant power (FRAP) assay. The results showed that A β (25-35) impaired step-through latency and time in dark compartment in passive avoidance task. In the MWM, A β (25-35) significantly increased escape latency and traveled distance. Borage administration attenuated the A β -induced memory impairment in both the passive avoidance and the MWM tasks. A β induced a remarkable decrease in antioxidant power (FRAP value) of hippocampus and borage prevented the decrease of the hippocampal antioxidant status. This data suggests that borage could improve the learning impairment and oxidative damage in the hippocampal tissue following A β treatment and that borage consumption may lead to an improvement of AD-induced cognitive dysfunction.
    Full-text · Article · Jun 2014 · BioMed Research International
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    • "“Cholinergic dysfunction” involves several mechanisms, not fully understood, but blocking cholinergic receptors may be one cause related to cognitive degeneration in AD patients (Terry et al., 1991; Van der Zee and Luiten, 1999). Amyloid toxicity directly affects neuronal physiology, particulary in cholinergic system, with biochemical alteration, neuroinflammation, deregulation of neuroprotective systems, resulting neurode-generation and behavioral alterations which show symptomatic and pathophysiological similarities to AD (Zussy et al., 2011). Thus, we examined the effects of HCW in Aβ-injected mice model. "
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    ABSTRACT: Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer's disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD.
    Full-text · Article · May 2014 · Biomolecules and Therapeutics
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Questions & Answers about this publication

  • Florian Duclot added an answer in Transgenic Rats:
    What are the best non-transgenic Alzheimer's disease rat models?

    I'm trying to study about non-transgenic rat models in alzheimer's disease and the information about non-transgenic rat model is less than transgenic rat model. 

    Florian Duclot

    If you're looking at a non-transgenic rat model of AD, have a look at the following publication (see end of message). As someone previously explained, modeling all aspects of the human pathology is complex and difficult, but this model incudes a wide range of AD-like symptoms (behavioral and molecular). Have a look at other publications from this group for more information.

    Hope this helps.

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      [Show abstract] [Hide abstract]
      ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25-35 (Aβ(25-35)) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled Aβ(25-35) peptide was used as negative control. The aggregated forms of Aβ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of Aβ(25-35) decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, Aβ(25-35), the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular Aβ(25-35) injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD.
      Full-text · Article · Jul 2011 · American Journal Of Pathology