Resilience in the suprachiasmatic nucleus: Implications for aging and Alzheimer's disease

Fernandez, Fabian-Xosé; Kaladchibachi, Sevag; Negelspach, David C.

doi:10.1016/j.exger.2021.111258

Cited by 9 publications

(8 citation statements)

References 142 publications

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“…[18][19][20][21] Conversely, the SCN, the locus of primary circadian clock in mammals, [22][23][24] is thought to be relatively resilient to AD, although disruptions in sleep and other circadian rhythms are increasingly acknowledged as early symptoms of AD. [25][26][27] The SCN is surrounded by the AH, of which little is known regarding its neurodegenerative vulnerability. Mouse brain slices containing cortex and SCN/AH region were isolated from healthy mice and incubated with either KV11 or G6W peptides (300 or 400 μM, respectively; see also Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…16,17 It was hypothesized that depending on the length and amino acid composition of the peptide, either cylindrin or a β-barrel could be formed. For example, Do et al showed by IMS-MS and molecular dynamics simulation that Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) forms an octameric β-barrel. 16 Because the glycine in the sixth position is essential to the structural integrity of toxic amyloid-like cylindrin assemblies, 5,14 it is logical to predict that a mutation of glycine to a bulky residue, such as tryptophan, would prevent cylindrin formation and alleviate cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Atomic view of an amyloid dodecamer exhibiting selective cellular toxic vulnerability in acute brain slices

et al. 2022

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Atomic structures of amyloid oligomers that capture the neurodegenerative disease pathology are essential to understand disease-state causes and finding cures. Here we investigate the G6W mutation of the cytotoxic, hexameric amyloid model KV11. The mutation results into an asymmetric dodecamer composed of a pair of 30 twisted antiparallel β-sheets. The complete break between adjacent β-strands is unprecedented among amyloid fibril crystal structures and supports that our structure is an oligomer. The poor shape complementarity between mated sheets reveals an interior channel for binding lipids, suggesting that the toxicity may be due to a perturbation of lipid transport rather than a direct disruption of membrane integrity. Viability assays on mouse suprachiasmatic nucleus, anterior hypothalamus, and cerebral cortex demonstrated selective regional vulnerability consistent with Alzheimer's disease. Neuropeptides released from the brain slices may provide clues to how G6W initiates cellular injury.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Atomic view of an amyloid dodecamer exhibiting selective cellular toxic vulnerability in acute brain slices

et al. 2022

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“…Having been in chronobiology for so many years, it still astounds me that we know so little about the functional outputs of the SCN. I consider it to be a gross oversight in our field because it continues to hold us back from better integrating into the medical community (Fernandez et al, 2021). We cannot claim a role for the circadian system in cognitive impairments such as Alzheimer's disease and then shrug when asked how the SCN influences the hippocampus, or feel that it is sufficient to appeal to oscillator misalignment and expect that to satisfy medical professionals.…”

Section: Resultsmentioning

confidence: 99%

Suppression of Circadian Timing and Its Impact on the Hippocampus

Ruby

2021

Front. Neurosci.

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In this article, I describe the development of the disruptive phase shift (DPS) protocol and its utility for studying how circadian dysfunction impacts memory processing in the hippocampus. The suprachiasmatic nucleus (SCN) of the Siberian hamster is a labile circadian pacemaker that is easily rendered arrhythmic (ARR) by a simple manipulation of ambient lighting. The DPS protocol uses room lighting to administer a phase-advancing signal followed by a phase-delaying signal within one circadian cycle to suppress clock gene rhythms in the SCN. The main advantage of this model for inducing arrhythmia is that the DPS protocol is non-invasive; circadian rhythms are eliminated while leaving the animals neurologically and genetically intact. In the area of learning and memory, DPS arrhythmia produces much different results than arrhythmia by surgical ablation of the SCN. As I show, SCN ablation has little to no effect on memory. By contrast, DPS hamsters have an intact, but arrhythmic, SCN which produces severe deficits in memory tasks that are accompanied by fragmentation of electroencephalographic theta oscillations, increased synaptic inhibition in hippocampal circuits, and diminished responsiveness to cholinergic signaling in the dentate gyrus of the hippocampus. The studies reviewed here show that DPS hamsters are a promising model for translational studies of adult onset circadian dysfunction in humans.

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“…Intensive pharmacological regimens (quetiapine + midazolam and quetiapine + midazolam + trazodone) have been demonstrated to improve sleep quality and cognitive function while minimizing side effects [23]. Similarly, studies have demonstrated that midazolam in combination with quetiapine improves sleep difficulties in Alzheimer's patients [32].…”

Section: Pharmacological Treatmentmentioning

confidence: 99%

The casual relationship between AD and sleep disorders

Wang¹,

Wu²

2022

HSET

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As people get older, organs inside our bodies are not as strong as before. Besides the illness from their body, many of the elders are worrying about another torture, Alzheimer’s disease (AD). For the old people who are suffering from AD, their brains cannot work as usual as before and most times, they cannot sleep as usual. Sleep disorder, which is a cause of Alzheimer's disease, is common among those patients who suffer from AD. This article analyzes the origins, whether other factors first triggered the loop, as well as the interaction between sleep disorders and AD forms a closed loop in which they interact and contribute to each other and list the pharmacological and non-pharmacological treatments for AD and sleep disorders, respectively.

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Resilience in the suprachiasmatic nucleus: Implications for aging and Alzheimer's disease

Cited by 9 publications

References 142 publications

Atomic view of an amyloid dodecamer exhibiting selective cellular toxic vulnerability in acute brain slices

Atomic view of an amyloid dodecamer exhibiting selective cellular toxic vulnerability in acute brain slices

Suppression of Circadian Timing and Its Impact on the Hippocampus

The casual relationship between AD and sleep disorders

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