Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

Abstract

In Alzheimer's disease increasing evidence attributes synaptic and cognitive deficits to soluble oligomers of amyloid β protein (Aβ), even prior to the accumulation of amyloid plaques, neurofibrillary tangles, and neuronal cell death. Here we show that within 1-2 hours picomolar concentrations of cell-derived, soluble Aβ induce specific alterations in pre-and postsynaptic morphology and connectivity in cultured hippocampal neurons. Clusters of presynaptic vesicle markers decreased in size and number at glutamatergic but not GABAergic terminals. Dendritic spines also decreased in number and became dysmorphic, as spine heads collapsed and/or extended long protrusions. Simultaneous time-lapse imaging of axon-dendrite pairs revealed that shrinking spines sometimes became disconnected from their presynaptic varicosity. Concomitantly, miniature synaptic potentials decreased in amplitude and frequency. Spine changes were prevented by blockers of nAChRs and NMDARs. Washout of Aβ within the first day reversed these spine changes. Further, spine changes reversed spontaneously by two days, because neurons acutely developed resistance to continuous Aβ exposure. Thus, rapid Aβ-induced synapse destabilization may underlie transient behavioral impairments in animal models, and early cognitive deficits in Alzheimer's patients.

Adenosine A2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

“…In fact, the only morphological change found in the hippocampus of A␤-injected rodents displaying memory deficits was the loss of synaptic markers, whereas neither overt neuronal damage nor astrogliosis nor microgliosis were observed, neither 15 nor 2 d after A␤ 1-42 administration. Accordingly, in cultured neurons (in which peripheral, vascular, glial, or immune influences are absent), we also found that exposure to A␤ caused first a synaptotoxicity (Roselli et al, 2005;Calabrese et al, 2007;Shankar et al, 2007;Evans et al, 2008), which is only later followed by overt neuronal damage. Further strengthening that A␤ causes direct effects on nerve terminals, we showed that A␤ indeed directly impairs synaptosomal function, as observed by others (Mattson et al, 1998;Arias et al, 2002).…”

Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

“…In light of several studies describing the neurotoxic effects of synthetic Aβ aggregates or cell-secreted Aβ oligomers (3,(5)(6)(7)(8)(15)(16)(17), we assessed the effects of such preparations on the neuritic cytoskeleton in an attempt to confirm the changes described above with natural dimers isolated from the AD cortex. We examined a synthetic human Aβ40 peptide in which serine 26 is mutated to cysteine (Aβ40 S26C), enabling the formation of stable, disulfidebonded dimers under oxidizing conditions (10,18).…”

Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases

“…Because of the easy maintenance and fast growth rate of these cells, 7PA2 culture medium has provided a convenient tool to investigate the biological activities of low-n Aβ oligomers. This led to the discovery that Aβ oligomers can inhibit hippocampal long-term potentiation (an electrophysiological measure of synaptic plasticity) (67,68), impair complex learned behavior in the live rat (69), and reduce the density of dendritic spines in cultured hippocampal neurons (70,71).…”