Article

Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice

Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Goettingen, von-Siebold-Str. 5, 37075, Göttingen, Germany.
Acta Neuropathologica (Impact Factor: 10.76). 01/2009; 116(6):647-55. DOI: 10.1007/s00401-008-0451-6
Source: PubMed

ABSTRACT

The accumulation of beta-amyloid (A beta) plaques and neurofibrillary tangles consisting of hyperphosphorylated tau protein are pathological features of Alzheimer's disease (AD) commonly modeled in mice using known human familial mutations; however, the loss of neurons also found to occur in AD is rarely observed in such models. The mechanism of neuron degeneration remains unclear but is of great interest as it is very likely an important factor for the onset of adverse memory deficits occurring in individuals with AD. The role of A beta in the neuronal degeneration is a matter of controversial debates. In the present study we investigated the impact of extracellular plaque A beta versus intraneuronal A beta on neuronal cell death. The thalamus and the frontal cortex of the APP/PS1KI mouse model were chosen for stereological quantification representing regions with plaques only (thalamus) or plaques as well as intraneuronal A beta (frontal cortex). A loss of neurons was found in the frontal cortex at the age of 6 months coinciding with the decrease of intraneuronal immunoreactivity, suggesting that the neurons with early intraneuronal A beta accumulation were lost. Strikingly, no neuron loss was observed in the thalamus despite the development of abundant plaque pathology with levels comparable to the frontal cortex. This study suggests that plaques have no effect on neuron death whereas accumulation of intraneuronal A beta may be an early transient pathological event leading to neuron loss in AD.

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    • "Sagittal brain sections of 5XFAD het and 5XFAD hom mice at 2, 5, and 9 months of age were stained with an A antibody detecting an N-terminal A epitope (A[N]). Relative amyloid load was quantified in the cortex, hippocampus, and thalamus as described earlier [17] (Fig. 5A–F). A significant increase in A plaque load was noted in 5XFAD hom compared to 5XFAD het mice in all analyzed brain regions at all time points (Cortex: 2 m: +232%; 5 m: +228%; 9 m: +32%; Hippocampus: 2 m: +615%; 5 m: +464%; 9 m: +52%; Thalamus: 2 m: +311%; 5 m: +101%; 9 m: +75%) (Fig. 5). "
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    ABSTRACT: According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβ x-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβ x-42 species appear to be the crucial players in AD etiology, the Aβ 2-x isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ 2-x in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ 2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.
    No preview · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
    • "Sagittal brain sections of 5XFAD het and 5XFAD hom mice at 2, 5, and 9 months of age were stained with an A antibody detecting an N-terminal A epitope (A[N]). Relative amyloid load was quantified in the cortex, hippocampus, and thalamus as described earlier [17] (Fig. 5A–F). A significant increase in A plaque load was noted in 5XFAD hom compared to 5XFAD het mice in all analyzed brain regions at all time points (Cortex: 2 m: +232%; 5 m: +228%; 9 m: +32%; Hippocampus: 2 m: +615%; 5 m: +464%; 9 m: +52%; Thalamus: 2 m: +311%; 5 m: +101%; 9 m: +75%) (Fig. 5). "
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    ABSTRACT: In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research.
    No preview · Article · Feb 2015 · Journal of Alzheimer's disease: JAD
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    • "Extensive research on the neurotoxic role of beta amyloid (Aβ) in its fibrillar form has demonstrated that it accumulates in the brain as extracellular insoluble plaques around neurons and glia (Kowalewski and Holtzman, 1999; Mucke and Selkoe, 2012). Later, this view changed when it was recognized that in Alzheimer's disease (AD) patients, cognitive impairment is poorly correlated with counts of " senile plaques " in cerebral gray matter either in patients (Blennow et al., 1996; Berg et al., 1998; Giannakopoulos et al., 2003, 2009) or in animal models (Puoliväli et al., 2002; Christensen et al., 2008; Watanabe et al., 2009; Zhang et al., 2012). More recently, in support of this, the initial etiopathogenetic hypothesis has been questioned by the failure of several clinical trials testing drugs targeting Aβ accumulation in the brain (Mangialasche et al., 2010). "
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    ABSTRACT: It has been well documented that β-amyloid peptide accumulation and aggregation in the brain plays a crucial role in the pathophysiology of Alzheimer’s disease (AD). However, a new orientation of the amyloid cascade hypothesis has evidenced that soluble forms of the peptide (sAβ) are involved in Aβ-induced cognitive impairment and cause rapid disruption of the synaptic mechanisms underlying memory. The primary aim of this study was to elucidate the effects of sAβ, acutely injected intracerebrally (i.c.v., 4 µM), on the short term and long term memory of young adult male rats, by using the novel object recognition task. Glutamatergic receptors have been proposed as mediating the effect of Aβ on synaptic plasticity and memory. Thus, we also investigated the effects of sAβ on prefrontal cortex (PFC) glutamate release and the specific contribution of N-methyl-D-aspartate (NMDA) receptor modulation to the effects of sAβ administration on the cognitive parameters evaluated. We found that a single i.c.v. injection of sAβ 2h before testing did not alter the ability of rats to differentiate between a familiar and a novel object, in a short term memory test, while it was able to negatively affect consolidation/retrieval of long term memory. Moreover, a significant increase of glutamate levels was found in PFC of rats treated with the peptide 2 h earlier. Interestingly, memory deficit induced by sAβ was reversed by a NMDA-receptor antagonist, memantine (5 mg/kg i.p), administered immediately after the familiarization trial (T1). On the contrary, memantine administered 30 min before T1 trial, was not able to rescue long term memory impairment. Taken together, our results suggest that an acute i.c.v. injection of sAβ peptide interferes with the consolidation/retrieval of long term memory. Moreover, such sAβ-induced effect indicates the involvement of glutamatergic system, proposing that NMDA receptor inhibition might prevent or lead to the recovery of early cognitive impairment.
    Full-text · Article · Sep 2014 · Frontiers in Behavioral Neuroscience
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