MEMOLOAD

Neurobiological Mechanisms of Memory Loss in Alzheimer's Disease

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 Obiettivo del progetto (Objective)

'The MEMOLOAD project will focus on the molecular and biological mechanisms underlying memory loss that occurs in Alzheimer’s disease, the leading cause of dementia and an enormous medical, social and economic challenge to Europe. Several lines of evidence point to accumulation of beta-amyloid peptide (Aß) in the brain as the key pathologic event in the disease. There is growing evidence that Aß causes memory loss by directly or directly interacting with the known key signalling pathways involved in memory consolidation. However, at present the data is fragmentary and consists mainly of single observations in particular models (cell culture, brain slice, in vivo). In most cases, we still lack the evidence that a clear molecular level interaction translates into memory impairment in vivo. The objective of this proposal is to elucidate the molecular level mechanisms by which accumulation of Aß in the brain results in impaired synaptic plasticity and memory loss. The MEMOLOAD consortium consists of a well-balanced mixture of the seven best available European research groups in terms of research experience on both the mechanisms of memory consolidation and the pathophysiology of Alzheimer’s disease. The current research topic is thus the primary research interest of all partners. MEMOLOAD will significantly contribute to a better understanding of brain memory mechanisms at the behavioural, network, synaptic and molecular levels and of dysfunction at all these levels in Alzheimer’s disease (AD). The knowledge acquired during the course of MEMOLOAD will translate into new validated in vitro and in vivo models for the memory impairing effect of Aß and will feed into industrial development leading to new therapies. The output of MEMOLOAD will include both identification of new drug targets and development of novel peptidomimetic compounds that neutralize the deleterious effects of most harmful Aß species.'

Introduzione (Teaser)

Alzheimer's disease is the leading cause of dementia. It presents an enormous medical, social, and economic challenge to Europe.

Descrizione progetto (Article)

To address this problem, the 'Neurobiological mechanisms of memory loss in Alzheimer's disease' (http://www.uef.fi/fi/MEMOLOAD (MEMOLOAD)) project focused on the molecular and biological mechanisms underlying memory loss. There is growing evidence that amyloid-beta peptide (Abeta) causes memory loss by directly or indirectly interacting with the signalling pathways involved in memory consolidation.

A consortium of the seven best available research groups worked together to identify at the molecular level how accumulation of Abeta impairs the flexibility, or plasticity, of brain synapses that results in memory loss. Secondly, the consortium is developing new peptidomimetric molecules that disrupt Abeta proliferation.

Researchers began by developing behavioural tasks sensitive to small changes in synaptic signalling and plasticity in the cerebral cortex and hippocampus. All participating laboratories then used these tasks to test the success of drug treatments on Abeta production in transgenic mouse models.

Next, the research focus switched from Abeta-induced changes in individual synapses to the impact on large neuronal populations and the entire neural network. Second, acute effects of Abeta on synaptic plasticity were compared to long-term changes in the brain. Finally, brain activity in rodents was measured as they performed a memory task to track changes in network communication.

Other experiments aimed at determining the direct and indirect effects of Abeta on two signalling pathways central to memory consolidation, developing synthetic Abeta compounds to be used for further study. The team also synthesised peptides to determine if they inhibit Abeta growth. While these peptides have not proven to be effective, scientists are continuing to look for other compounds.

This research has contributed significantly to understanding of brain memory mechanisms. The consortium also has added research tools, including new animal models for testing and imaging methods to screen for Abeta-induced changes. Over time, the hope is to find an effective therapy to halt the disease's progression.