Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer's disease

Kalinin, Sergey; Gavrilyuk, Vitaliy; Polak, Paul; Vasser, Robert; Zhao, Jie; Heneka, Michael T.; Feinstein, Douglas L.

doi:10.1016/j.neurobiolaging.2006.06.003

Cited by 184 publications

(166 citation statements)

References 46 publications

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“…This association is consistent with the fact that although defective 5-HT or NA neurotransmission does not affect cognitive function, the combined antagonism of both systems or the addition of anticholinergic compounds can induce cognitive defects (Kenton et al, 2007). Significantly, toxin-induced degeneration of NA neurons in APP (amyloid precursor protein) Tg mice exacerbates amyloid pathology and cognitive dysfunction (Heneka et al, 2006;Kalinin et al, 2007), and chronic administration of 5-HT reuptake inhibitor attenuates pathology and behavioral abnormalities in the 3XT-gAD mice (Nelson et al, 2007). Thus, severe degeneration of MAergic neurons may have significant impact on the onset and progression of both the behavioral and the pathological abnormalities in the APPswe/PS1⌬E9 mice and in AD.…”

Section: Discussionsupporting

confidence: 69%

“…A simple explanation is that the pathological changes in cortex, such as amyloid deposition and inflammation, leads to degeneration of the brainstem MAergic neurons. Significantly, degeneration of NA neurons may contribute to the progression of amyloid pathology in brain (Heneka et al, 2006;Kalinin et al, 2007), and abnormalities in MAergic systems may underlie cognitive and noncognitive abnormalities of AD. Given this background, we hypothesized that A␤ pathology may be linked to degeneration of the MAergic system in the APPswe/PS1⌬E9 mouse model of amyloidosis (Jankowsky et al, 2004;Savonenko et al, 2005b).…”

Section: Introductionmentioning

confidence: 99%

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Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Liu¹,

Yoo²,

Savonenko³

et al. 2008

J. Neurosci.

180

169

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␤-Amyloid (A␤) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of A␤ pathology, including A␤ deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the A␤ neurotoxicity indicated by in vitro studies, mouse models with significant A␤ deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that A␤ pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1⌬E9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain A␤ deposition in the APPswe/ PS1⌬E9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (ϳ50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local A␤ or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of A␤ pathology develops progressive MAergic neurodegeneration occurring in AD cases.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Liu¹,

Yoo²,

Savonenko³

et al. 2008

J. Neurosci.

180

169

View full text Add to dashboard Cite

show abstract

“…Moreover, locus ceruleus injury has been shown to accelerate forebrain amyloid deposition and neural injury in a murine model of Alzheimer disease (Heneka et al, 2006;Kalinin et al, 2007). Having demonstrated in the present study that oxygenation patterns, as observed in sleep apnea, can significantly injure the locus ceruleus, it will be of interest to look for disease interactions between obstructive sleep apnea (present in Ͼ10% of elderly humans) and Alzheimer's disease.…”

mentioning

confidence: 63%

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Zhu¹,

Fenik²,

Zhan³

et al. 2007

J. Neurosci.

171

117

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The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/ reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/ reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury were next assessed in major wake-active neural groups. Hypoxia/reoxygenation exposure for 8 weeks resulted in vacuolization in the perikarya and dendrites and markedly impaired c-fos activation response to enforced wakefulness in both noradrenergic locus ceruleus and dopaminergic ventral periaqueductal gray wake neurons. In contrast, cholinergic, histaminergic, orexinergic, and serotonergic wake neurons appeared unperturbed. Six month exposure to hypoxia/reoxygenation resulted in a 40% loss of catecholaminergic wake neurons. Having previously identified NADPH oxidase as a major contributor to wake impairments in hypoxia/reoxygenation, the role of NADPH oxidase in catecholaminergic vulnerability was next addressed. NADPH oxidase catalytic and cytosolic subunits were evident in catecholaminergic wake neurons, where hypoxia/reoxygenation resulted in translocation of p67 phox to mitochondria, endoplasmic reticulum, and membranes. Treatment with a NADPH oxidase inhibitor, apocynin, throughout hypoxia/reoxygenation exposures conferred protection of catecholaminergic neurons. Collectively, these data show that select wake neurons, specifically the two catecholaminergic groups, can be rendered persistently impaired after long-term exposure to hypoxia/reoxygenation, modeling sleep apnea; wake impairments are irreversible; catecholaminergic neurons are lost; and neuronal NADPH oxidase contributes to this injury. It is anticipated that severe obstructive sleep apnea in humans destroys catecholaminergic wake neurons.

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“…and S.S.S., personal observations). In addition, the limbic forebrain of TTR-deficient mice exhibits significantly elevated levels of noradrenaline (Sousa et al, 2004), a catecholamine neurotransmitter that has been shown to modulate A␤ burden in a transgenic mouse model of AD (Kalinin et al, 2007). Finally, because retinol and thyroid hormones are essential for normal mammalian brain physiology and are particularly critical during development (Porterfield and Hendrich, 1993) and because TTR is the only thyroid hormone-binding protein found at a substantial level in the CSF (Herbert et al, 1986), it is possible that TTR reduction could cause developmental abnormalities.…”

Section: Increased Levels Of Cerebral A␤ Levels In Brains Of Hemizygomentioning

confidence: 99%

Accelerated A Deposition in APPswe/PS1 E9 Mice with Hemizygous Deletions of TTR (Transthyretin)

Choi

Leight

Lee

et al. 2007

Journal of Neuroscience

123

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A cardinal pathological lesion of Alzheimer's disease (AD) is the deposition of amyloid ␤ (A␤) in the brain. We previously reported that exposing transgenic mice harboring APPswe/PS1⌬E9 transgenes to an enriched environment resulted in reduced levels of A␤ peptides and deposition, findings that were correlated with an increase in the expression of TTR, encoding transthyretin (TTR). TTR is expressed at high levels in the choroid plexus and known to bind A␤ peptides and modulate their aggregation in vitro and in vivo. To explore the impact of TTR expression on A␤ levels and deposition in vivo, we crossed ceAPPswe/PS1⌬E9 transgenic mice to mice with genetic ablations of TTR. We now report that the levels of detergent-soluble and formic acid-soluble levels of A␤ and deposition are elevated in the brains of ceAPPswe/PS1⌬E9/TTR؉/؊ mice compared with age-matched ceAPPswe/PS1⌬E9/TTR؉/؉ mice. Moreover, A␤ deposition is significantly accelerated in the hippocampus and cortex of ceAPPswe/PS1⌬E9/TTR؉/؊ mice. Our results strongly suggest that TTR plays a critical role in modulating A␤ deposition in vivo.

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Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer's disease

Cited by 184 publications

References 46 publications

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Accelerated A Deposition in APPswe/PS1 E9 Mice with Hemizygous Deletions of TTR (Transthyretin)

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