Amyloid beta from axons and dendrites reduces local spine number and plasticity

Abstract

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer’s disease. Amyloid beta (Aβ), a peptide secreted in an activity-modulated manner by neurons, has been implicated in the pathogenesis of Alzheimer’s disease by removing dendritic spines, sites of excitatory synaptic transmission. However, issues regarding the subcellular source of Aβ, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. In rat organotypic slices, we found that acute overproduction of either axonal or dendritic Aβ reduced spine density and plasticity at nearby (~5–10 µm) dendrites. 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 NMDA receptor blockade. Notably, only 30–60 min blockade of Aβ overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Aβ at dendrites or axons acts locally to reduce the number and plasticity of synapses.

Trafficking and Proteolytic Processing of APP

“…A major secretion site of Ab seems to be distal axons/synapses (Lazarov et al 2002;Sheng et al 2002), but recently it was reported that Ab can be secreted from axons and dendrites and can elicit local effects on neighboring neurons ( Fig. 7C; Wei et al 2010). A detailed analysis aimed at determining the ratio of axonally versus dendritically secreted Ab, using for example cultured neurons in compartmentalized chambers, has not been performed.…”

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

“…Synapse loss is the most robust correlate of AD-associated cognitive deficits. In both AD patients and animal models of this disease, the greastest synapse loss is near senile plaques, indicating a link between Aβ pathology and synaptotoxicity in vivo [7,8] . Furthermore, AβOs have been www.chinaphar.com Zhang LL et al Acta Pharmacologica Sinica npg shown to downregulate the levels of two synaptic proteins, postsynaptic density-95 (PSD-95) and synaptophysin [9] .…”

Glutamate receptors in preclinical research on Alzheimer's disease: Update on recent advances

“…The increase in release probability was associated with reduced paired-pulse facilitation such that excitatory synapses behaved like low-pass filters, facilitating low frequency activation of AMPA receptors in hippocampal slices. How this presynaptic facilitatory action relates to the putative negative feedback postsynaptic actions of endogenously-generated human Aß (Hsieh et al , 2006, Wei et al , 2010 is not clear. If confirmed, caution will be needed in the use of anti-Aß therapies that might interfere with such physiological processes.…”

“…Li et al (2009) reported that cell-derived oligomeric human Aß acutely increased extracellular glutamate concentrataion in hippocampal slices. Whereas low nanomolar concentrations of these oligomers reduced the amplitude of AMPA receptor-mediated (Cerpa et al , 2010, Kessels et al , 2010, Ronicke et al , 2010). …”

“…plasticity and initiate spine loss in hippocampal slice culture within 1-3 days (Wei et al, 2010). Similarly, the relative importance of synaptic versus extrasynaptic glutamate receptors and their trafficking between different compartments in mediating Aß action needs to be integrated with our growing knowledge of their roles in cognitive decline in other neurodegenerative diseases such as Huntington's disease (Hardingham and Bading, 2010).…”