Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction

Abstract

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Abeta, the alphav integrin extracellular cell matrix-binding protein and the cytokine TNFalpha (tumour necrosis factor alpha) type-1 death receptor mediate Abeta oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFalpha or genetic knockout of TNF-R1s (type-1 TNFalpha receptors) prevented Abeta-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to alphav-containing integrins abrogated LTP block by Abeta. Protection against the synaptic plasticity-disruptive effects of soluble Abeta was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Abeta oligomers in preclinical AD.

Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP

“…Interestingly although LTP was unaffected in TNF receptor-deficient mice, LTD could not be recorded in these animals (Albensi and Mattson, 2000). To our knowledge, this is the first report of a similar change in dentate gyrus in vivo; although TNF-␣ has been implicated as a factor which contributes to the inhibition of LTP induced by A␤ in vivo (Rowan et al, 2007). As previously reported, the age-related decrease in LTP was attenuated in rats treated with rosiglitazone (Loane et al, 2009) and the evidence suggested that the effect was mediated by IL-4 which is released from astrocytes .…”

“…Thus predictably, IL-1␤ inhibits LTP in vitro and in vivo (Curran et al, 2003;Murray and Lynch, 1998) and H 2 O 2 has also been shown to exert a similar detrimental effect, at least at low concentrations in young animals (Kamsler and Segal, 2003;Vereker et al, 2001). An inhibitory effect of TNF-␣ on LTP has also been reported (Butler et al, 2004;Cumiskey et al, 2007;Tancredi et al, 1992) and it has been identified as a key mediator in the inhibitory effect of A␤ on LTP (Rowan et al, 2007). Recent evidence has indicated that when inflammatory and oxidative stress are inhibited by overexpression of mitochondrial transcription factor A (TFAM), the age-related decrease in LTP in CA1 is ameliorated (Hayashi et al, 2008), while eicosapentaenoic acid, which exerts anti-inflammatory and antioxidative effects similarly restores LTP in aged rats Martin et al, 2002).…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…Nearly a decade ago TNF was reported to alter synaptic transmission in hippocampal slices (Tancredi et al, 1992). Several years later (Wang et al, 2005b;Rowan et al, 2007), it was shown that this earlier observation explained the ability of A␤, through TNF, to do the same. Other researchers expanded the roles of TNF in this context (Pickering et al, 2005;Stellwagen et al, 2005).…”

Inherent Anti-amyloidogenic Activity of Human Immunoglobulin γ Heavy Chains

“…Given the unique anti-amyloidogenic activity of HC F1, we used this molecule to investigate the in vivo therapeutic potential of free HCs using a rodent model of A␤ oligomer impairment of hippocampal LTP, which is a measurable correlate of long term memory and learning (45)(46)(47). Fig.…”