Inflammation and Alzheimer's disease.

Sleep improves the consolidation of both declarative and non-declarative memories. Diekelmann and Born discuss the potential mechanisms through which slow wave sleep and rapid eye movement sleep support system and synaptic consolidation. Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory, depending on the specific conditions of learning and the timing of sleep. Consolidation during sleep promotes both quantitative and qualitative changes of memory representations. Through specific patterns of neuromodulatory activity and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement (REM) sleep support system consolidation and synaptic consolidation, respectively. During SWS, slow oscillations, spindles and ripples — at minimum cholinergic activity — coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity — at high cholinergic and theta activity — might favour the subsequent synaptic consolidation of memories in the cortex.

The memory function of sleep

Recent evidence suggests that some brain areas act as hubs interconnecting distinct, functionally specialized systems. These nexuses are intriguing because of their potential role in integration and also because they may augment metabolic cascades relevant to brain disease. To identify regions of high connectivity in the human cerebral cortex, we applied a computationally efficient approach to map the degree of intrinsic functional connectivity across the brain. Analysis of two separate functional magnetic resonance imaging datasets (each n = 24) demonstrated hubs throughout heteromodal areas of association cortex. Prominent hubs were located within posterior cingulate, lateral temporal, lateral parietal, and medial/lateral prefrontal cortices. Network analysis revealed that many, but not all, hubs were located within regions previously implicated as components of the default network. A third dataset (n = 12) demonstrated that the locations of hubs were present across passive and active task states, suggesting that they reflect a stable property of cortical network architecture. To obtain an accurate reference map, data were combined across 127 participants to yield a consensus estimate of cortical hubs. Using this consensus estimate, we explored whether the topography of hubs could explain the pattern of vulnerability in Alzheimer's disease (AD) because some models suggest that regions of high activity and metabolism accelerate pathology. Positron emission tomography amyloid imaging in AD (n = 10) compared with older controls (n = 29) showed high amyloid-beta deposition in the locations of cortical hubs consistent with the possibility that hubs, while acting as critical way stations for information processing, may also augment the underlying pathological cascade in AD.

https://www.jneurosci.org/content/jneuro/29/6/1860.full.pdf

Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease

Oxidative stress hypothesis in alzheimer's disease

Copper, iron and zinc in Alzheimer's disease senile plaques

Altered processing of the amyloid precursor protein (APP) is a central event in the formation of amyloid deposits in the brains of individuals with Alzheimer's disease. To investigate whether cellular APP processing is controlled by cell-surface neurotransmitter receptors, human embryonic kidney (293) cell lines were transfected with the genes for human brain muscarinic acetylcholine receptors. Stimulation of m1 and m3 receptor subtypes with carbachol increased the basal release of APP derivatives within minutes of treatment, indicating that preexisting APP is released in response to receptor activation. Receptor-activated APP release was blocked by staurosporine, suggesting that protein kinases mediate neurotransmitter receptor-controlled APP processing.

http://science.sciencemag.org/content/sci/258/5080/304.full.pdf

Release of Alzheimer Amyloid Precursor Derivatives Stimulated by Activation of Muscarinic Acetylcholine Receptors

To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.

https://www.pnas.org/content/pnas/89/5/1671.full.pdf

Evidence for a membrane defect in Alzheimer disease brain.

Activation of protein kinase C inhibits cellular production of the amyloid beta-protein.

Proteolytic processing of the beta-amyloid protein precursor (APP) is regulated by cell-surface receptors. To determine whether neurotransmitter release in response to neuronal activation regulates APP processing in brain, we electrically depolarized superfused rat hippocampal slices and measured soluble APP derivatives released into the superfusate. Electrical depolarization caused a rapid increase in the release of both neurotransmitters and amino-terminal APP cleavage products. These derivatives lacked the APP carboxyl terminus and were similar to those found in both cell culture media and human cerebrospinal fluid. Superfusate proteins including lactate dehydrogenase were not changed by electrical depolarization. The release of amino-terminal APP derivatives increased with increasing stimulation frequencies from 0 to 30 Hz. The increased release was inhibited by the sodium-channel antagonist tetrodotoxin, suggesting that action-potential formation mediates the release of large amino-terminal APP derivatives. These results suggest that neuronal activity regulates APP processing in the mammalian brain.

Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices.

http://wurtmanlab.mit.edu/static/pdf/911.pdf

Roger Nitsch

Papers

Release of Alzheimer Amyloid Precursor Derivatives Stimulated by Activation of Muscarinic Acetylcholine Receptors

Evidence for a membrane defect in Alzheimer disease brain.

Activation of protein kinase C inhibits cellular production of the amyloid beta-protein.

Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices.

Serotonin 5-HT2a and 5-HT2c Receptors Stimulate Amyloid Precursor Protein Ectodomain Secretion