Neurological diseases that result in the degeneration of synapses culminate in severe cognitive deficits and (behavioral disturbances. These dementing illnesses present increasing medical and socioeconomic problems and raise a wide range of fundamental neuroscientific questions. Alzheimer's disease (AD) is the main cause of age-related dementia and its prevalence is increasing rapidly due to the increasing number of elderly in our population. AD is associated with a prominent degeneration of synapses and with an abnormal accumulation of amyloid beta peptides (AB) in the brain. A-beta is derived from the amyloid protein precursor (APP), which is enriched in synapses. The precise relationship between APP, A-beta, and synaptic loss remains obscure. The current proposal aims to shed light on this relationship. We previously used the platelet-derived growth factor (PDGF) beta chain promoter to express human APP (hAPP) in neurons of transgenic mice. In these studies, we focused on the density of synaptophysin-immunoreactive presynaptic terminals because the loss of these structures correlates well with cognitive decline in AD. High levels of neuronal A-beta production in PDGF-hAPP mice resulted in a decrease of presynaptic terminals and elicited major deficits in synaptic transmission.
In Aim 1, we will investigate whether the profile of synaptic protein alterations in PDGF-hAPP mice resembles that in AD brains, affecting some proteins more than others, and we will examine whether these alterations are preceded or followed by changes in pre- or postsynaptic neurons.
In Aim 2, we will assess to what extent the development of synaptic, alterations in PDGF-hAPP mice depends on the activity of the protein tyrosine kinase Fyn, ablation of which has been shown to prevent A-beta-induced neurotoxicity in tissue culture.
In Aim 3, we will immunize PDGF-hAPP mice, with A-beta to determine whether this approach can induce the clearance of synaptotoxic A-beta species and inhibit synaptic degeneration.
In Aim 4, we will investigate the relationship between synaptic alterations and behavioral deficits in PDGF-hAPP mice and determine whether the latter can also be prevented or reversed by A-beta vaccination. Achieving these aims will help assess the potential usefulness of novel therapeutic strategies for this most prevalent neurodegenerative disorder. It will also advance our understanding of the function of synaptic proteins in synapse loss and degeneration, which is the focus of RFA NS-01-002.
Showing the most recent 10 out of 35 publications
