Muistijälkien kirjoittaminen aivojen kovalevylle unen aikana takkuilee Alzheimerin taudissa

”Why do we need to sleep?” is still a question with no unambiguous answer. New findings from brain research suggest that one important function of sleep is to enable the transfer of temporary memories from deep brain structures to long-term storage in the cerebral cortex. This article describes from step to step how this process is thought to occur at the level of a single neuron and neural networks. The transfer of episodic memories from the hippocampus in the medial temporal lobe to the cerebral cortex explains a well-known paradox: an elderly person with Alzheimer’s disease can remember even small details of decade-old events but fails to remember what happened only a few hours ago. Transfer of the memory engram particularly during sleep and typical sleep fragmentation at early stages of Alzheimer’s disease can at least partly account for the poor memory of recent events. A better understanding of the underlying factors and mechanisms can help us develop new treatments to strengthen the weak parts in this chain of events and thereby enhance remembering of new events

Mikrogliasolut hoidon kohteeksi hermoston rappeumasairauksissa : TREM2-signalointi keskeisenä useassa sairaudessa

Teema : neuroimmunologia

Brain Aging: Changes in the Nature of Information Coding by the Hippocampus

Advanced age in rats is associated with a decline in spatial memory capacities dependent on hippocampal processing. As yet, however, little is known about the nature of age-related alterations in the information encoded by the hippocampus. Young rats and aged rats identified as intact or impaired in spatial learning capacity were trained on a radial arm maze task, and then multiple parameters of the environmental cues were manipulated to characterize the changes in firing patterns of hippocampal neurons corresponding to the presence of particular cues or the spatial relationships among them. The scope of information encoded by the hippocampus was reduced in memory-impaired aged subjects, even though the number of neurons responsive to salient environmental cues was not different from that in young rats. Furthermore, after repeated manipulations of the cues, memory-intact aged rats, like young rats, altered their spatial representations, whereas memory-impaired aged rats showed reduced plasticity of their representation throughout testing. Thus changes in hippocampal memory representation associated with aging and memory loss can be characterized as a rigid encoding of only part of the available information

Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Purified intravenous immunoglobulin (IVIG) obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs) against β-amyloid (Aβ) peptides accumulating in the brains of Alzheimer's disease (AD) patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses.</p> <p>Methods</p> <p>We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of Aβ burden was analyzed with <it>ex vivo </it>assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD <it>in vivo</it>.</p> <p>Results</p> <p>IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits <it>ex vivo</it>. IVIG enhanced microglia-mediated Aβ clearance <it>ex vivo</it>, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ clearance we observed have potential relevance <it>in vivo </it>since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest concentrations in the hippocampus and bound selectively to Aβ deposits in co-localization with microglia.</p> <p>Conclusions</p> <p>Our results demonstrate that IVIG promotes recognition and removal of natively formed brain Aβ deposits by primary microglia involving natural Aβ Abs in IVIG. These findings may have therapeutic relevance <it>in vivo </it>as IVIG penetrates through the blood-brain barrier and specifically binds to Aβ deposits in brain parenchyma.</p

Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme

The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which could not be detected in IDE knock-down cells. Further analysis of the underlying molecular mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity. The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet, revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for example in coconut oil, might be beneficial in preventing or treating Alzheimer’s disease

Significance of developmental meningeal lymphatic dysfunction in experimental post-traumatic injury

Publisher Copyright: © 2022 The AuthorsPeer reviewe

Sleep-State Dependent Alterations in Brain Functional Connectivity under Urethane Anesthesia in a Rat Model of Early-Stage Parkinson's Disease

Parkinson's disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra, leading to striatal dopamine depletion. A partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion causes 40-60% dopamine depletion in the lesioned rat striatum, modeling the early stage of PD. In this study, we explored the connectivity between the brain regions in partially 6-OHDA lesioned male Wistar rats under urethane anesthesia using functional magnetic resonance imaging (fMRI) at 5 weeks after the 6-OHDA infusion. Under urethane anesthesia, the brain fluctuates between the two states, resembling rapid eye movement (REM) and non-REM sleep states. We observed clear urethane-induced sleep-like states in 8/19 lesioned animals and 8/18 control animals. 6-OHDA lesioned animals exhibited significantly lower functional connectivity between the brain regions. However, we observed these differences only during the REM-like sleep state, suggesting the involvement of the nigrostriatal dopaminergic pathway in REM sleep regulation. Corticocortical and corticostriatal connections were decreased in both hemispheres, reflecting the global effect of the lesion. Overall, this study describes a promising model to study PD-related sleep disorders in rats using fMRI.Peer reviewe