Final Report Summary - MEMORIES (Development, characterisation and validation of new and original models for Alzheimer's Disease)
Alzheimer's disease (AD) is a neurological disorder and is the most common form of dementia in later life. It is estimated that, by 2050, the number of people aged 80 years or older will approach 370 million worldwide and that 50 % of those aged 85 years and older will be affected by AD.
AD is clinically characterised by short-term memory loss and cognitive dementia, associated with language and behavioural impairments. The pathological hallmarks of AD include the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFT), neurodegeneration and cell loss. One severely affected region of the AD brain is the basal forebrain (which includes the nucleus basalis of Meynert, the medial septum and the diagonal band of Broca), a group of cholinergic neurons that are connected to areas of the neocortex and hippocampus and that are important for learning, memory and attention.
The complex degeneration in AD has been fertile ground for the formulation of hypotheses on the pathogenesis of the disorder. Methodological advances allowed shedding light on alterations of the various neurotransmitter systems in the AD brain. The discovery of the degeneration in the basal forebrain, in the context of experimental evidence for the role of acetylcholine in memory, have led to the development of a symptomatic therapy for AD, based on enhanced acetylcholine availability determined by cholinesterase inhibitors.
In the field of Alzheimer's disease it is assumed that the familial early onset and the sporadic late onset forms of the disease are clinically equivalent, with the exception of the much earlier onset. However, there is a gap in translating the mechanistic information available for FAD into useful concepts for LOAD. Part of this gap is due to the issue of mouse models.
Using a multidisciplinary approach, a panel of mouse models were produced and analysed for the presence of neurodegeneration. AD11 anti- NGF, which already represent a good model for sporadic AD, were crossed to mice in which pro-convertases or SorLA receptors were knocked out. Additional mice were created, expressing mutated form of pro-NGF or in which knockout of TrkB, TrkA and NGF was achieved.
The mice were then analysed using standardised methodology for neuroanatomy and behavioural analysis. Early on they anticipated that blocking different signalling pathways will help in ameliorating the currently available experimental mouse models, and will also be useful for developing new therapeutic tools for this disease and strengthening European competitiveness in the war against AD.
The study confirmed the validity of the approach used by the different partners to dissect mechanisms underlying the onset of neurodegeneration linked to LOAD and provided new information on different models and different mechanisms highly relevant for human sporadic AD.
AD is clinically characterised by short-term memory loss and cognitive dementia, associated with language and behavioural impairments. The pathological hallmarks of AD include the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFT), neurodegeneration and cell loss. One severely affected region of the AD brain is the basal forebrain (which includes the nucleus basalis of Meynert, the medial septum and the diagonal band of Broca), a group of cholinergic neurons that are connected to areas of the neocortex and hippocampus and that are important for learning, memory and attention.
The complex degeneration in AD has been fertile ground for the formulation of hypotheses on the pathogenesis of the disorder. Methodological advances allowed shedding light on alterations of the various neurotransmitter systems in the AD brain. The discovery of the degeneration in the basal forebrain, in the context of experimental evidence for the role of acetylcholine in memory, have led to the development of a symptomatic therapy for AD, based on enhanced acetylcholine availability determined by cholinesterase inhibitors.
In the field of Alzheimer's disease it is assumed that the familial early onset and the sporadic late onset forms of the disease are clinically equivalent, with the exception of the much earlier onset. However, there is a gap in translating the mechanistic information available for FAD into useful concepts for LOAD. Part of this gap is due to the issue of mouse models.
Using a multidisciplinary approach, a panel of mouse models were produced and analysed for the presence of neurodegeneration. AD11 anti- NGF, which already represent a good model for sporadic AD, were crossed to mice in which pro-convertases or SorLA receptors were knocked out. Additional mice were created, expressing mutated form of pro-NGF or in which knockout of TrkB, TrkA and NGF was achieved.
The mice were then analysed using standardised methodology for neuroanatomy and behavioural analysis. Early on they anticipated that blocking different signalling pathways will help in ameliorating the currently available experimental mouse models, and will also be useful for developing new therapeutic tools for this disease and strengthening European competitiveness in the war against AD.
The study confirmed the validity of the approach used by the different partners to dissect mechanisms underlying the onset of neurodegeneration linked to LOAD and provided new information on different models and different mechanisms highly relevant for human sporadic AD.
