Evidence of intraneuronal Aβ accumulation preceding tau pathology in the entorhinal cortex

Welikovitch, Lindsay A.; Carmo, Sonia Do; Maglóczky, Zsófia; Szocsics, Péter; Lőke, János; Freund, Tamás F.; Cuello, A. Claudio

doi:10.1007/s00401-018-1922-z

Cited by 65 publications

(66 citation statements)

References 81 publications

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“…In fact, PSEN1 E280A ChLNs exhibited a significantly higher p-TAU/ t-TAU ratio than WT PSEN1 ChLNs at 4 days post transdifferentiation. These observations imply that Aβ 42 signaling precedes TAU phosphorylation [75,76]. Moreover, these findings comply with the notion that Aβ 42 accumulation affects TAU pathology [77].…”

Section: Discussionsupporting

confidence: 88%

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Soto-Mercado

Mendivil-Perez

Vélez-Pardo

et al. 2019

Preprint

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies.Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra-and extracellular A42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.

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Section: Discussionsupporting

confidence: 88%

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Soto-Mercado

Mendivil-Perez

Vélez-Pardo

et al. 2019

Preprint

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“…Although the McGill-R-Thy1-APP rat is a valuable model for understanding the inflammatory effects that are specific to iAβ, it does not fully reflect the neuropathological environment of the human central nervous system (CNS). Given that progressive iAβ accumulation has also been observed in the human brain (11)(12)(13)(14)(15)40), we posited that Aβburdened neurons may produce a similar, plaque-independent inflammatory signal within the human entorhinal cortex and hippocampus. We therefore compared the cell-specific expression of CCL2 in the human medial temporal lobe of subjects with and without extracellular plaques.…”

Section: Expression Of Ccl2 In the Human Medial Temporal Lobe Shifts mentioning

confidence: 96%

mentioning

confidence: 99%

“…Prior to the formation of extracellular plaques and tau neurofibrillary tangles (NFT), Aβ peptides and oligomers appear to accumulate within neurons of disease-vulnerable brain regions (11)(12)(13)(14)(15). This soluble pool of intraneuronal Aβ (iAβ) also increases in an age-dependent manner within the entorhinal cortex, a brain region regarded as the origin of AD neuropathological spread (13,15). Despite the fact that Aβ oligomers represent the most toxic amyloid species within the brain (16)(17)(18)(19)(20), the effects of progressive iAβ build-up have scarcely been studied, and information on how this soluble pool may influence AD susceptibility is lacking.…”

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confidence: 99%

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Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

Welikovitch

Carmo

Maglóczky

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Chronic inflammation during Alzheimer’s disease (AD) is most often attributed to sustained microglial activation in response to amyloid-β (Aβ) plaque deposits and cell death. However, cytokine release and microgliosis are consistently observed in AD transgenic animal models devoid of such pathologies, bringing into question the underlying processes that may be at play during the earliest AD-related immune response. We propose that this plaque-independent inflammatory reaction originates from neurons burdened with increasing levels of soluble and oligomeric Aβ, which are known to be the most toxic amyloid species within the brain. Laser microdissected neurons extracted from preplaque amyloid precursor protein (APP) transgenic rats were found to produce a variety of potent immune factors, both at the transcript and protein levels. Neuron-derived cytokines correlated with the extent of microglial activation and mobilization, even in the absence of extracellular plaques and cell death. Importantly, we identified an inflammatory profile unique to Aβ-burdened neurons, since neighboring glial cells did not express similar molecules. Moreover, we demonstrate within disease-vulnerable regions of the human brain that a neuron-specific inflammatory response may precede insoluble Aβ plaque and tau tangle formation. Thus, we reveal the Aβ-burdened neuron as a primary proinflammatory agent, implicating the intraneuronal accumulation of Aβ as a significant immunological component in the AD pathogenesis.

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“…In stark contrast, the other post mortem pathological hallmark of Alzheimer’s, Aβ plaques, is largely overlooked as a contributor to the LC disease spectrum due to the relatively belated presentation of such pathology in this brain region, in most cases only at Braak stages V-VI (Braak et al 2011). However, the importance of the Aβ system in contributing to the initial stages of Alzheimer’s could be a significant oversight due to recent evidence indicating that intraneuronal AβO accumulation precedes tau pathology in the entorhinal cortex, which alongside the LC, presents earliest with Alzheimer’s pathology (Welikovitch et al 2018). Furthermore, compelling data indicate that AβO, rather than Aβ plaques impart the predominant toxic burden for this pathway (Ghag et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

Kelly

Seifi

et al. 2020

Preprint

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Amyloid β oligomers (AβO) are potent modulators of two key Alzheimer's pathological processes, namely synaptic dysfunction and tau tangle formation in various brain regions. Remarkably, the impact of AβO in one of the earliest brain regions to exhibit Alzheimer's pathology, the locus coeruleus (LC), remains to be determined. Of particular importance is the effect of AβO on the excitability of individual LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all severely compromised in Alzheimer's. Using a mouse model of increased Aβ production (APP-PSEN1), together with correlative histopathological analyses in post mortem Alzheimer's patient samples, we determined the impact of Aβ pathology on various correlates of LC neuronal integrity. AβO immunoreactivity in the LC of APP-PSEN1 mice was replicated in patient samples, presenting as individual clusters located both intraneuronally, in mitochondrial compartments, as well as extracellularly in association with inhibitory synapses. No specific signal was detected in either patient control or wild type mouse samples. Accompanying this AβO expression profile was LC neuronal hyperexcitability and indicators of oxidative stress in APP-PSEN1 mice. LC hyperexcitability arose from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA-A receptor (GABA A R) α 3 subunit. Importantly, this altered LCα 3-GABA A R expression profile overlapped with AβO expression in both APP-PSEN1 mice and Alzheimer's patient samples. Finally, strychninesensitive glycine receptors (GlyRs) remained resilient to AβO-induced changes and their activation reversed LC hyperexcitability. Alongside this first demonstration of 4 AβO expression in the LC of Alzheimer's patients, the study is also first to reveal a direct association between AβO and LC neuronal excitability. GlyR-α3-GABA A R modulation of AβO-dependent LC hyperexcitability could delay the onset of cognitive and psychiatric symptoms arising from LC-NA deficits, thereby significantly diminishing the disease burden for Alzheimer's patients. particular relevance to the LC, and its early presentation of Alzheimer's pathology, is the emerging synergistic role of AβO in tau tangle formation (Pickett et al. 2019; Shin et al. 2019b). Intriguingly, while notable LC neuronal loss, attributed to tauopathy, is a core feature in Alzheimer's (Chan-Palay and Asan 1989), there appears to be discordance between the onset of such pathology, and LC neurodegeneration (Weinshenker 2018). Given such considerable evidence, it is reasonable to speculate that in the LC, initial, pre-symptomatic insults in the form of tau tangle and AβO interactions, cooperate to set in motion a range of pathological changes such as synaptic dysfunction, oxidative stress (De Felice et al. 2007) and altered LC excitability (Sanchez-Padilla et al. 2014). Such changes are likely to prove crucial in terms of the long-term viabili...

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Evidence of intraneuronal Aβ accumulation preceding tau pathology in the entorhinal cortex

Cited by 65 publications

References 81 publications

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

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