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Memory loss in Alzheimer disease: underlying mechanisms and therapeutic targets

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Mechanisms of memory loss in dementia

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.

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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.

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