MEMOSAD

Memory loss in Alzheimer disease: underlying mechanisms and therapeutic targets

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 Obiettivo del progetto (Objective)

'MEMOSAD aims at defining the molecular mechanisms of Abeta- and Tau-induced synaptotoxicity and at developing disease-modifying therapeutics for the prevention of memory loss in Alzheimer disease (AD). Insoluble aggregates of the two proteins provide the pathological hallmarks of this incurable brain disorder. Early stage AD is characterized by a remarkably pure impairment of declarative memory and several lines of evidence suggest that this memory impairment is independent of the insoluble aggregates, does not require neuronal death and is caused by subtle and transient synaptic changes. The toxic Abeta and Tau species that cause synaptic dysfunction, their mechanism of toxicity and the link between both pathologies remain largely unknown, but recent data suggest that Abeta accumulation triggers Tau pathology. Consequently, primary neuronal cultures and animal models (C.elegans,zebrafish,mouse) will be employed to define the pathologic pathways leading from Abeta through Tau to synaptotoxicity. Initial experiments will investigate the effect of well-defined Abeta species on long term potentiation, synaptic morphology, gene expression, Tau phosphorylation/aggregation, axonal transport and behaviour. Similarly, we will investigate the functional consequences of Tau misfunction, aggregation, hyperphosphorylation and missorting in various cell culture systems (retinal ganglion cells, primary hippocampal neurons, organotypical slices) and animal models, especially with regard to intraneuronal trafficking and synaptic function. Once the toxic Abeta and Tau species are known and their mechanism of toxicity are defined, we will investigate how these pathways interact. Unravelling the pathologic pathways that lead from Abeta through Tau to synaptotoxicity and memory loss should reveal novel points for therapeutic intervention. Our aim is to deliver 3 or 4 validated therapeutic targets and at least 2 compounds with demonstrated therapeutic efficacy in mouse models of AD.'

Introduzione (Teaser)

Two proteins play an instrumental role in the cognitive deficit associated with Alzheimer's disease (AD) and other forms of dementia. EU-funded scientists have now developed targeted therapies with great promise for millions of sufferers.

Descrizione progetto (Article)

Memory is largely mediated by signalling between neurons at synapses, the location where neurons are in very close conjunction with each other. Synaptic dysfunction thus plays a role in memory loss commonly seen in most forms of dementia and is a hallmark of AD.

On a molecular level, AD is characterised by abnormal insoluble aggregates of two proteins, the amyloid-beta peptide (Abeta) and tau. The former contributes to extracellular neuritic plaques, and the latter to intracellular neurofibrillary tangles. Pathological changes in AD suggest that Abeta accumulation triggers tau pathology, but mechanisms are largely unknown.

Scientists initiated the EU-funded project 'Memory loss in Alzheimer disease: Underlying mechanisms and therapeutic targets' (MEMOSAD) to identify the toxic Abeta and tau species, their mechanisms of toxicity and their interrelationship. The ultimate goal was identification of potential therapeutic targets to combat the devastating and irreversible memory loss in AD and related pathologies.

Researchers employed commonly used primary neuronal cultures and animal models to untangle the mystery. They investigated the effects of well defined Abeta species and the functional consequences of aberrant tau processing and aggregation on a number of molecular substrates of synaptic function.

MEMOSAD members collaborated to successfully generate Abeta aggregation inhibitors and demonstrated memory improvements in two rodent models. Scientists also validated the use of tau immunotherapy in treating AD and other tau-related pathologies. Results showed a reduction in aggregated tau and a delay in the onset of cognitive deficits following immunisation.

The identified targets represent an important breakthrough in treating or slowing the progression of AD. This may also prove to be a valuable diagnostic tool or biomarker for AD, other forms of dementia and related neurodegenerative disorders such as Parkinson's disease. AD and dementia are global public health priorities. MEMOSAD has made a significant contribution to ameliorating their impact on the lives of patients, caregivers and overburdened health care systems.