Alzheimer's Disease and LTP Impairment

Alzheimer's disease (AD), a neurodegenerative disorder, is most well-known for its characteristic symptom of dementia. Other symptoms include loss of reasoning, insight and even a decline in language abilities. There have been many neuromolecular pathologies that have been thought to be implicated in the symptoms associated with AD, which include but are not limited to neurofibrillary tangles that have been thought to be composed of hyperphosphorylated tau protein and Amyloid β plaques that are created through the aggregation of amyloid-B oligomers (Aβ proteins), particularly the spliced version Aβ42, which is the main contributor to the production of these AB diffuse plaques in vivo [1]

The function of AB aggregations in their role with LTP was clarified when it was shown that LTP could be inhibited via injection of AB oligomers into hippocampal slices [2]. Experiments of AB injections in vivo not only showed that the aggregates still inhibited LTP [3], but also showed that the injections led to poor performances by mice in learning paradigm tests [4]. These findings were strengthened through a paper which showed that the injection of an AB aggregation inhibitor, SEN1269 was able to rescue LTP deficits in vitro as well as in vivo [5].
There have been numerous explanations for the molecular mechanism by which AB oligomers are able to inhibit LTP. Rammes et al. 2011 (please see [6] ) have attributed inhibition of LTP to the ability that AB plaques have in inducing excitotoxicity via mGlu5 receptors and excessive NMDA receptor function. Whereas, Selkoe, 2008 ( please see [7] ) attributed LTP inhibition to the reduced synaptic spines due to the reduced intracellular Ca influx which favoured LTD over LTP. Lastly, Vitolo et al., 2002 [8] showed that upon treatment of hippocampal cultured cells with AB there was an increased inhibition of PKA and subsequently, a reduction of CREB phosphorylation and action.

Alzheimer's Disease and Synaptic Dysfunction
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Neuron, Walsh et al. 2004

1. Electrophysiology – Evidence for the effects of AB plaques on LTP

1.1 Injection of AB into hippocampal slices inhibits LTP and reduces synaptic density

Effect of AB oligomers on LTP
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Nomura et al., 2012 showed that the injection of AB40 oligomers to hippocampal slices was able to
reduce the level of EPSCs after the maintenance of LTP had been achieved via theta burst stimulation (TBS).
The addition of the mGLUR5 antagonist MPEP prevents the inhibitory action of the AB oligomers on the LTP deficit.

There are many approaches by which the cognitive impairment in AD may be investigated. From an anatomical approach, it is well known that the density of neurons and spines, in particular areas of the brain are reduced with the progression of AD [9] [1]. Previous studies have shown that the decrease in the volume of areas of the brain, specifically in the hippocampus was the result of the negative interaction with the AB oligomers and synapses. These oligomers were shown to preferentially target excitatory synapses in which they were found to be co-localized with the synaptic scaffolding protein PSD-95 and glutamate receptor subunits, ultimately resulting in the loss of synapses [10]. However, it is important to note that there is minimal neuronal loss with AB plaque accumulation and that the correlation between this and the degree to which memory is impaired is fairly weak [4] therefore indicating there are additional factors playing a role in the disruption of memory in AD.
In light of electrophysiology there have been many studies which were able to show that AB oligomers had disrupted LTP [2] [3] while preserving LTD [11] thereby that the presence of AB plaques had tilted the tendency towards inhibitory synaptic activity, promoting the instability of selected synapses [10].

1.2 Injection of AB impairs LTP in vivo

It was found that the injection of AB42 was able to impair LTP induction in a dosage-dependent manner. AB40 was effective at impairing LTP than the AB42 oligomers as they possess different biochemical properties. [2] [3]. The aversive effects on LTP have also been shown in vivo, in an experiment where human AB oligomers grown in a conditioned medium were injected into the hippocampus of mice. LTP was induced via high frequency stimulation (HSF) of the CA1 region while the mice were under anesthesia. It was shown that the AB injected were able to completely block LTP, which again, was not due to any form of reduction in baseline transmission [3]. It has also been shown that in addition to LTP impairment, AB plaques reduced the propensity for the reversal of LTD, therefore promoting the destabilization of dendritic spines. Wang et al., (2002) [11] explain this result to be due to fact that LTD is NMDAR independent in the dentate gyrus, where their particular subset of experiments were conducted, and that the AB deleterious interaction at the synapse has been due to interaction with certain NMDAR subunits, NR2A, NR2B [10].

AB40 more effective at reducing LTP than AB42
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Nomura et al., 2012 showed that the 40 amino acid spliced version of the
AB oligomer had more significant results for inhibiting LTP

1.3 Injection of AB-oligomer inhibitor rescues learning impairment induced by AB injection

To further solidify the evidence that AB oligomers are able to impair LTP, a recent study by Scopes et al., (2012) [5] was
able to demonstrate in an in vitro assay that the injection of a AB aggregate inhibitor, SEN1269 was able to reduce LTP deficits in vitro.
The injection was able to reverse the negative effects of AB injection which originally
caused the inhibition of LTP recording in the CA1, upon HFS in the Schaffer collaterals before treatment with SEN1269.

Rescue of LTP with AB-oligomer inhibitor
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The injection of AB42 oligomers was able to prevent the maintenance of LTP which was induced via
HFS. Whereas the injection of SEN1269, the AB oligomer inhibitor was able to rescue the
reduction in the fEPSP amplitude due to the injection of the AB oligomers (Scopes et al., 2012).

2. Behavioural analysis of B-amyloid effect on learning and plasticity

2.1 Injection of AB reduced performance on learning and memory paradigm

A procedure known as the alternating lever cyclic ratio (ALCR) test has been shown to successfully assess the cognitive functioning of rats. The ultimate purpose of the test is for the rats to learn a sequence of lever pressing requirements though reinforcement [4]. In the experiments conducted by Cleary et al., (2005) [4] rats were trained and then were surgically injected with the medium containing AB oligomers, or a control medium without the oligomers. Upon retesting the rats in the ALCR paradigm, it was shown that the injection of the AB oligomers was able to disrupt this previously learned complex behaviour in a transient manner, whereas the injection of the AB monomers, in addition to the control medium without the AB oligomers did not have a significant effect on cognitive performance. This study was significant because it was able to show the association of the memory impairment the AB plaques had on memory without the characteristic neurodegeneration normally present in AD. In addition to this, other papers have showed the association between the injection of AB and the hindrance of cognitive and memory function in learning paradigms such as the radial arm maze and the Morris water maze (Sweeney et al., 1997; McDonald et al., 1994).

Effect of AB oligomers on learning and memory task performance
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Cleary et al., 2005 showed that the rats that were injected with an AB containing medium (7PA2)
performed the worst on the learning and memory test and produced the most errors (bar 3).
Bars 5 and 6 represent rats injected with AB – medium whose performances have been
rescued after conjunctive injection with the AB- inhibitor SEN1269. Bars 1 and 2 represent the
performances of the control mice injected with medium not containing any AB or inhibitors

2.2 Rescue of performance on learning and memory paradigm after injection with AB- oligomer inhibitor

As mentioned in the electrophysiology section, the drug SEN1269 was able to reduce LTP deficits in vitro by reversing the by reversing the electrophysiological profile of AB oligomers. In adjunct to this, Scopes et al., (2012) [5] also investigated the effect of SEN1269 on the performance of rats that were injected with AB oligomers. After the rats were trained for the ALCR paradigm, they were then either injected with a control medium containing np AB oligomers, or with a medium which contained the AB oligomers after which performance on the ALCR test was assessed. Furthermore, some of the mice which were injected with the AB oligomers were then injected with the AB aggregate inhibitor SEN1269 and performance on ALCR paradigm was assessed again. It was found that after learning, the mice which had the AB injections produced the most errors in the ALCR paradigm. Whereas, the mice which received the AB oligomer injections in concordance with SEN1269 showed learning/memory errors at a level that was not only significantly less that the AB- injected mice, but also at a level identical to the mice which were injected with the control medium which contained no AB oligomers . This evidence thus points not only towards the confirmation in which AB oligomers have in impairing LTP and perhaps even memory, but also to the potential that drugs such as SEN1269 or other AB aggregate inhibitor have in being possible therapeutic avenues for AD memory deficits.

3. Molecular mechanisms involved in the inhibition of LTP due to the presence of AB

3.1 Inhibition of LTP due to PKA/CREB inhibition

Throughout the neuroscience literature exists different theories about the molecular mechanism by which AB is able to impair synaptic transmission and LTP, ultimately leading to cognitive deficits. One prominent theory explains the inhibition of LTP due to the inhibitory effects of AB plaques in the PKA/CREB signalling pathway. It is well known that CREB and PKA are not only important for the proper functioning of LTP, but are also crucial for the survival of neurons. The transcription factor CREB, along with its other co-translational partners such as CBP are able to prevent neuronal death through activity dependent processes which ultimately aid in the transcription of pro-life proteins including neurotrophic factors such as BDNF, a crucial protein in maintaining the survival of neurons [12]. Therefore if AB plaques are able to interfere with the downstream signaling that allows the transduction between CREB activation and the production of progrowth signals, the obvious result would be neuronal death. There have been multiple identified neuronal pathways such as the Ca2+/CamKII and cAMP/PKA pathways which promote translation via CREB convergence [12]. Downstream signaling cascades proceeded by glutamatergic receptors attributes PKA responsible for the phosphorylation of CREB in the progression of LTP from the early to late phase [8]
Vitolo et al., 2002 assessed the effects of different levels of AB on the ability of PKA to phosphorylate CREB, thus promoting the transition from the early to late phase of LTP by treating hippocampal neurons with AB oligomers and measuring various downstream consequences. Antibodies were used to mark an epitope of the PKA regulatory subunit, and specifically for the phosphorylated version of CREB at SER-133. PKA catalytic activity was inferred through two things, the first, calculating the levels of present CREB detected by the antibody that was specific for only the phosphorylated version of CREB, catalyzed by PKA. The second being the levels of the regulatory subunit of PKA, as its presence would imply lack of PKA catalytic activity because cAMP binding to the regulatory subunit targets it for degradation.
There were 2 parts of the experiment, one part involved the molecular component in assessing CREB phosphorylation and thus activation, and the other that involved the electrophysiology which showed that the LTP inhibition was accomplished via PKA/CREB pathway inhibition. Experimentally this was determined by the fact that the addition of AB to the hippocampal slices showed an accumulation of the regulatory subunit of PKA, indicating its lack of CREB phosphorylation activity, and also showed that even in the presence of glutatmate, when AB was additionally present pCREB levels were significantly reduced. In conjunction to this, it was also shown that AB reduced fEPSPs therefore intergrating the finding of reduced PKA catalytic activity and lowered pCREB levels with the impairment of LTP to the presence of AB.

Correlating AB levels with PKA activity
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Higher regulatory subunit of PKA presence implies lack of PKA activity.
After the injection of AB, as time progressed, higher levels of the regulatory
subunit was positively correlated with increased hourly presence of AB oligomers (Vitolo et al., 2002).

LTP impairment due to AB - mechanism involving PKA
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Theory showing that with excess AB (on the left) AC activity is reduced/inhibited,
resulting in the down regulation of CAMP, and thus more regulatory PKA subunit available and not
targeted for degradation, resulting in inactive PKA and thus lack of CREB activity (Vitolo et al., 2002).

3.2 Other molecular mechanisms of the inhibition of LTP

Although there are many other theories for mechanisms by which AB oligomers are able to impair LTP, not all of them are well understood. A second theory involves the action through mGLUR5 receptors(see [6] ). The toxicity of AB is administered through its ability to bind to mGLURs, NMARs, as well as other scaffolding proteins including PSD95. It was proven that the inhibition of LTP is mediated though the overactivation of mGluRs due to evidence that showed that the mGLUR negative allosteric modulator, MPEP was able to reduce LTP deficits induced by AB injection therefore blocking AB-mediated inhibition of LTP. One other theory worth mentioning is that NMDARs are required for the pathophysiology of the AB oligomers. AB works by reducing NMDAR mediated Ca2+ currents, and this reduction in Ca2+ influx causes favourable activation of calcineurin, which favours the balance towards LTD as opposed to LTP ( See [6] and [7] ).

Possible Mechanisms of LTP impairment due to AB
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See (Sekole, 2008)
1. Selkoe, D. J. Alzheimer ’ s Disease : Genes , Proteins , and Therapy. 81, 741–766 (2001).
2. Nomura, I., Takechi, H. & Kato, N. Intraneuronally injected amyloid β inhibits long-term potentiation in rat hippocampal slices. J. Neurophysiol. 107, 2526–31 (2012).
3. Walsh, D. M. et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–9 (2002).
4. Cleary, J. P. et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79–84 (2005).
5. Scopes, D. I. C. et al. Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity. Br. J. Pharmacol. 167, 383–92 (2012).
6. Rammes, G., Hasenjäger, A., Sroka-Saidi, K., Deussing, J. M. & Parsons, C. G. Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology 60, 982–90 (2011).
7. Selkoe, D. J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–13 (2008)
8. Vitolo, O. V et al. Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. U. S. A. 99, 13217–21 (2002).
9. Walsh, D. M. & Selkoe, D. J. Deciphering the Molecular Basis of Memory Failure in Alzheimer ’ s Disease. 44, 181–193 (2004).
10. Wilcox, K. C., Lacor, P. N., Pitt, J. & Klein, W. L. Aβ oligomer-induced synapse degeneration in Alzheimer’s disease. Cell. Mol. Neurobiol. 31, 939–48 (2011).
11. Wang, H.-W. et al. Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 924, 133–40 (2002).
12. Dawson, T., Ginty D. (2002). NEWS & VIEWS CREB family transcription factors inhibit neuronal suicide Neurodenerative disorders such as Huntington disease lead to neuronal cell death in discrete regions of brain . A, 8(5), 450–452.

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