Abundance of Aβ5-xlike immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer’s disease

Guzmán, Erika Avendaño; Bouter, Yvonne; Richard, Bernhard Clemens; Lannfelt, Lars; Ingelsson, Martin; Paetau, Anders; Verkkoniemi-Ahola, Auli; Wirths, Oliver; Bayer, Thomas A.

doi:10.1186/1750-1326-9-13

Cited by 23 publications

(25 citation statements)

References 55 publications

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“…However, in studies on postmortem AD and mild cognitively impaired patients immunoreactivity of intracellular Aβ 42 (iAβ 42 ) has been identified in neurons of the hippocampus and entorhinal cortex (Gouras et al, 2000; Mori et al, 2002), the 2 main brain regions affected in early AD pathology. These findings have been corroborated by results from transgenic mouse models (Guzman et al, 2014; Youmans et al, 2012; for review see; LaFerla et al, 2007), leading to the overall hypothesis of iAβ accumulation as an early triggering event in the AD progression preceding senile plaques (Kuo et al, 2001; LaFerla et al, 2007; Oakley et al, 2006). Intracellular Aβ-driven effects on neuronal firing might therefore be one of the earliest detectable triggers of the AD pathology preceding and predisposing to synaptic deficits.…”

Section: Introductionmentioning

confidence: 62%

Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

Scala

Fusco

Ripoli

et al. 2015

Neurobiology of Aging

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Amyloid β-protein (Aβ) pathologies have been linked to dysfunction of excitability in neurons of the hippocampal circuit, but the molecular mechanisms underlying this process are still poorly understood. Here, we applied whole-cell patch-clamp electrophysiology to primary hippocampal neurons and show that intracellular Aβ42 delivery leads to increased spike discharge and action potential broadening through downregulation of A-type K+ currents. Pharmacologic studies showed that caspases and glycogen synthase kinase 3 (GSK-3) activation are required for these Aβ42-induced effects. Extracellular perfusion and subsequent internalization of Aβ42 increase spike discharge and promote GSK-3-dependent phosphorylation of the Kv4.2 α-subunit, a molecular determinant of A-type K+ currents, at Ser-616. In acute hippocampal slices derived from an adult triple-transgenic Alzheimer’s mouse model, characterized by endogenous intracellular accumulation of Aβ42, CA1 pyramidal neurons exhibit hyperexcitability accompanied by increased phosphorylation of Kv4.2 at Ser-616. Collectively, these data suggest that intraneuronal Aβ42 accumulation leads to an intracellular cascade culminating into caspases activation and GSK-3-dependent phosphorylation of Kv4.2 channels. These findings provide new insights into the toxic mechanisms triggered by intracellular Aβ42 and offer potentially new therapeutic targets for Alzheimer’s disease treatment.

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Section: Introductionmentioning

confidence: 62%

Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

Scala

Fusco

Ripoli

et al. 2015

Neurobiology of Aging

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“…Immunohistochemical analyses using Aβ 5-x selective antibodies confirmed the presence of Aβ 5-x peptides in brain tissues samples from sporadic AD patients showing immunoreactivity primarily in vascular deposits (88,92). In cases from individuals harboring FAD-associated APP or PSEN1 mutations, both vascular and parenchymal deposits were detected, while in mouse models such as 5XFAD, APP/PS1KI, or 3xTg Aβ 5-x , immunoreactivity was confined to extracellular plaques (92).…”

Section: Aβ 5-xmentioning

confidence: 79%

N-Terminally Truncated Aß Peptide Variants in Alzheimer’s Disease

Wirths

Zampar

Weggen

2019

Alzheimer’s Disease

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The accumulation and aggregation of amyloid-β (Aβ) peptides in the brain is believed to be the initial trigger in the molecular pathology of Alzheimer' s disease (AD). In addition to the widely studied full-length Aβ peptides (mainly Aβ 1-40 and Aβ 1-42), a variety of amino-terminally truncated (N-truncated) peptides, such as Aβ pE3-x and Aβ 4-x , have been detected in high abundance in autopsy samples from sporadic and familial AD patients. N-truncated Aβ species adopt specific physicochemical properties resulting in a higher aggregation propensity and increased peptide stability, which likely account for their neurotoxic potential. The presence of N-truncated Aβ peptides in transgenic mouse models of AD and the selective overexpression of specific N-truncated variants in the murine brain have facilitated their investigation in relevant in vivo settings. In this chapter, we address the pathological relevance of N-truncated Aβ peptide species and summarize the current knowledge about the enzymatic activities that might be involved in their generation.

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“…These N-truncations were detected in Aβ deposits of sporadic and familial AD [29, 62, 63, 72, 90, 94]. Using mass spectrometry and Western blot analysis of sporadic AD and familial AD cases (M146V PS1 or KM670/671NL APP ), Aβ 5–40/42 was one of the detected N-truncated species.…”

Section: Full-length Aβ Is a Physiological Peptide With A Role In Lonmentioning

confidence: 99%

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

2014

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Although N-truncated Aβ variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer’s disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer’s disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Aβ peptides based on mounting evidence that they may represent better targets than full-length Aβ. In addition to Aβ peptides starting with an Asp at position 1, a variety of different N-truncated Aβ peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Aβ, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Aβs dominate full-length Aβ in the brains of Alzheimer’s patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides

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Abundance of Aβ5-xlike immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer’s disease

Cited by 23 publications

References 55 publications

Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

N-Terminally Truncated Aß Peptide Variants in Alzheimer’s Disease

Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

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