Alzheimer's disease (AD), the main cause of age-related dementia, is increasing in prevalence due to the increasing number of elderly in our population. AD is associated with prominent impairments of neurons and synapses and with an abnormal accumulation of amyloid-B peptides (AB) in the brain. AB, which is derived from the amyloid precursor protein (APP), appears to play a causal role in AD, although it remains uncertain how it erodes cognitive functions and how this process can be prevented or reversed. The results we obtained during the preceding funding period have begun to shed light on these questions. We determined that human APP (hAPP) transgenic mice producing high levels of human Af5 in the brain have an AD-like pattern of synaptic alterations (previous Aim 1), that the enzyme Fyn is involved in some AB-dependent synaptic alterations (previous Aim 2), that premature mortality and neuronal deficits in hAPP mice can be prevented or delayed by the genetic modulation of Fyn or apolipoprotein E (previous Aim 3), and that the extent of cognitive deficits in hAPP mice is tightly linked to the neuronal depletion of factors that are regulated by excitatory synaptic activity (previous Aim 4). Some of these factors were also depleted in corresponding neuronal populations of humans with AD. These results provide a solid foundation for the current application and underline that we are in a good position to advance this interesting area of research. Here we propose to determine how exactly hAPP/Abeta interacts with Fyn-related signaling cascades to cause neuronal impairments (new Aim 1), whether the pharmacogenetic inhibition of Fyn can prevent and reverse neuronal deficits in hAPP mice (new Aim 2), whether hAPP/Abeta-dependent neuronal alterations are caused by an imbalance of excitatory and inhibitory synaptic activities (new Aim 3), and whether the pharmacological or genetic manipulation of neurotransmitter receptors or Fyn-related signaling pathways can prevent and reverse behavioral deficits in hAPP mice (new Aim 4). This study could reveal how increased levels of AB impair important cognitive functions such as learning and memory. It could also resolve whether these impairments can be prevented or reversed by therapeutic manipulation of synaptic activity and neuronal signaling. Ultimately, our study may provide useful guidance in the development of drugs to maintain and improve memory and other cognitive functions in AD.
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