Commentary (Research Highlights)

Stephen      D. Skaper

Abstract

Alzheimers disease (AD) is a debilitating neurodegenerative disorder characterized pathologically by the presence of extracellular senile plaques and intracellular neurofibrillary tangles. The main protein components of senile plaques are amyloid-β peptides (Aβ), secreted proteolytic derivatives of the amyloid precursor protein (APP). Excessive synaptic loss is thought to be one of the earliest events in AD, and synaptic loss is an excellent correlate with memory loss. Aβ oligomers bind to synaptic sites and remove dendritic spines. Consistent with these structural abnormalities, over-expression of APP leads to Aβ secretion and loss of spines on neurons overproducing APP that phenocopies quantitatively the effects of oligomeric Aβ addition at concentrations reached in the brains of individuals with AD; these neurons also show depressed glutamatergic transmission. Given the memory deficits observed in AD, it is notable that soluble Aβ oligomers impair long-term potentiation (a synaptic model of memory) and memory, which can be ameliorated by treatment with antibodies to Aβ or small molecules that inhibit Aβ aggregation. However, the subcellular source (pre- vs postsynaptic compartments) of Aβ, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. For example, it is not known if increased Aβ production in one neuron will affect structural plasticity in a nearby neuron. To better understand the interaction between Aβ and synaptic function, Wei and colleagues sought to identify the subcellular sites from which Aβ acts. APP and its derivatives, as well as components of the APP-processing enzymes β- and γ-secretase, have been detected in axons and dendrites. However, detecting effects originating from axonally or dendritically produced Aβ has been challenging. Wei et al. reasoned that if Aβ overproduction could cause spine loss in APP-over-expressing neurons, then neighboring neurons close to Aβ-containing structures may also be exposed to higher levels of secreted Aβ and therefore lose their spines. The authors isolated the sites of increased Aβ production by selectively expressing APP in pre- or postsynaptic neurons, and then used two-photon laser-scanning imaging to monitor the synaptic deficits caused by such dendritic or axonal Aβ. They found that either dendritic or axonal Aβ overproduction was sufficient to cause local spine loss and compromise plasticity in the nearby dendrites of neurons that did not express Aβ. The production of Aβ and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Aβ (but not its production) were sensitive to N-methyl-D-aspartate receptor blockade. These findings indicate that continuous overproduction of Aβ at dendrites or axons acts locally to reduce the number and plasticity of synapses. One caveat in the study of Wei et al. is that acute production or delivery of Aβ was employed, and the effects observed may not be entirely representative of events that occur in a chronic condition such as AD. Nevertheless, the observed effects in spine reduction were similar in magnitude and pharmacological sensitivity to effects produced by concentrations of Aβ estimated to occur in AD brain. It is possible that production of Aβ in axons or dendrites leads to secretion of additional toxic agents or prevents normal synaptic function and thereby leads to the local effects observed. Identifying the local target(s) of Aβ that leads to reduction of spines and their plasticity will be crucial to elucidating the mediators of these synaptic effects, and possibly the development of new therapeutic strategies.