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


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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Available from: Thomas A Bayer, Oct 10, 2015
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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.
    Frontiers in Behavioral Neuroscience 09/2014; 8(332). DOI:10.3389/fnbeh.2014.00332 · 3.27 Impact Factor
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    • "The following antibodies were applied: 4G8 (Covance, 1:10.000) (Christensen et al., 2008), OC (generous gift of Glabe and Kayed, 1:1000) (Kayed et al., 2007) and Aβ [N] (IBL, 1:500) (Christensen et al., 2010) against Aβ, 22C11 (Millipore, 1:1000) and 23850 (generous gift of G. Multhaup, 1:500) against human APP, G2-10 (Millipore, 1:500) and Aβ 40 (Synaptic Systems, #218203, 1:500) against Aβ 40, Aβ 42 (Synaptic Systems, #218703, 1:250), N3pE against pyroglutamate-modified Aβ (American Research Products, 1:250) (Wirths et al., 2009), kinesin light chain 1 (KLC1, Santa Cruz, sc-25735, 1:100) as well as anti-NF-200 (Millipore, 1:1000) and an antibody detecting phosphorylated APP at position T668 (anti-pT668; Cell Signaling Technologies, 1:500). Primary antibodies were incubated overnight in a humid chamber at room temperature followed by incubation with biotinylated secondary antibodies (DAKO). "
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    ABSTRACT: Abnormalities and impairments in axonal transport are suggested to strongly contribute to the pathological alterations underlying AD. The exact mechanisms leading to axonopathy are currently unclear, but it was recently suggested that APP expression itself triggers axonal degeneration. We used APP transgenic mice and crossed them on a hemi- or homozygous PS1 knock-in background (APP/PS1KI). Depending on the mutant PS1 dosage, we demonstrate a clear aggravation in both plaque-associated and plaque-distant axonal degeneration, despite of an unchanged APP expression level. Amyloid-β (Aβ) peptides were found to accumulate in axonal swellings as well as in axons and apical dendrites proximate to neurons accumulating intraneuronal Aβ in their cell bodies. This suggests that Aβ can be transported within neurites thereby contributing to axonal deficits. In addition, diffuse extracellular Aβ deposits were observed in the close vicinity of axonal spheroids accumulating intracellular Aβ, which might be indicative of a local Aβ release from sites of axonal damage.
    Frontiers in Aging Neuroscience 06/2014; 6:139. DOI:10.3389/fnagi.2014.00139 · 4.00 Impact Factor
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    • "These findings are corroborated by previous mouse models expressing full-length mutant APP. For example, APP/PS1KI mice exhibit neuron loss in the CA1 region of the hippocampus (Casas et al., 2004; Breyhan et al., 2009), the frontal cortex (Christensen et al., 2008), and in distinct cholinergic nuclei (Christensen et al., 2010). The APP/PS1KI model is characterized by age-dependent accumulation of heterogeneous N-terminal truncated Aβ peptides with Aβ 4–42 being one of the most abundant variants (Casas et al., 2004). "
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    ABSTRACT: One of the central research questions on the etiology of Alzheimer's disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next-generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneuronal Aβ aggregation, neuron loss, and behavioral deficits. (2) The Tg4-42 model expresses N-truncated Aβ4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEGs) were identified and subsequently verified by quantitative PCR. Nineteen DEGs were identified in pre-symptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss.
    Frontiers in Aging Neuroscience 04/2014; 6:75. DOI:10.3389/fnagi.2014.00075 · 4.00 Impact Factor
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