- Amyloid beta protein restores hippocampal long term potentiation: a central role for cholesterol?


Essential role for Ab in the mechanisms of synaptic function, plasticity, learning and memory remains to be intriguing and yet not disproved issue.

Such status quo illustrates an inability of Alzheimer’s neuroscience research community to validate amyloid hypothesis despite of intense research and major fields’ research funds allocated to it [4WEB+, 83, 84]. Since anti-amyloid vaccination was halted more then a year ago [4, 84] the question of whether the amyloid hypothesis is true approach for Alzheimer’s disease cure was sounded by many scientists (See Refs. 4WEB+, 85WEB+ for bibliography details). This is especially important because associated with the amyloid dogma competing financial interests and bias apparently retard the development of several other promising approaches [4WEB+,84, 85, 86]. The sad reality became illuminated on March 26, 2003 when Neuron (a major neuroscience journal) published a feature electrophysiological study on APP and Ab synaptic function [54]. This article by Kamenetz et al. was published near three years after it was first submitted and communicated at the Society for Neuroscience Annual Meeting in 2000 [54WEB+].

The three early electrophysiological studies reported Ab-mediated increase of LTP in rat dentate gyrus in in vitro experiments. Thus, it was shown [23] that whereas acute treatment of young rat (70-120 days) hippocampal slices with the low concentration (100-200 nM) of bath applied Ab1-40 did not change basal synaptic transmission, there was an increase in tetanus induced LTP. Moreover, intracellular (100 nM, via the recording pipette) or bath (200 nM) application of Ab1-40 triggered the slow onset potentiation of the NMDA receptor-mediated synaptic currents [24] in the hippocampal slices from young rats (70-120 g weight), and did not affect the basal AMPA receptor-mediated transmission, resting membrane potential or input resistance of the granule cells. It is very unfortunate that the authors oversight these two articles [23, 24] in their later publication on the neurotoxicity of Ab co-authored by a major proponent of the amyloid cascade hypothesis [73]. Similar results (of Ab being a beneficial molecule for synaptic function) were presented by Schulz, who showed no effect of Ab1-42 on AMPA currents, and demonstrated the increase of NMDA currents by the peptide [52]. This report proposed that Ab peptides (Ab1-42, Ab1-28 and Ab1-40) increase the probability of LTP under the paradigm that induced little LTP in control slices [52].

Another recent report [86], presented data on Ab1-42 and Ab25-35 inhibition of hippocampal LTP at the concentration of 200nM to 1mM and no effect at 20 nM. This paper, however, employed different from earlier reports [23, 24, 52] protocol (particularly, Sprague-Dawley, not Wistar, rats; 300C recording temperature; stimulus duration of 0.1 msec delivered through sharpened monopolar tungsten electrodes; the decline of bath-applied peptide just prior to the tetanic stimulation), and missed detailed consideration of Ab1-40, also proposed in the article (despite of the lack of experimental data) to inhibit the hippocampal LTP.

Several other articles reported on Ab infusion into the rat brain followed by electrophysiological [87, 88, 89, 90] or behavioral analysis [91, 92, 93]. The paper of Cullen et al. [87] showed no effect of low concentration of Ab1-40 (0.4 or 3.5 nmol in 5 ml, equal to the I.V. injection of 5 ml of 0.8 mg/ml solution for 3.5 nmol Ab1-40) on the ability to induce LTP in hippocampal slices in vitro, and the delayed (presented 24 and 48 hrs after the injection and not observed 75 min after injection) reduction in the NMDA receptor-mediated responses recorded in vivo. It is important to note that the other study concluded that “NMDA receptor regulation by amyloid-beta does not account for its inhibition of LTP in rat hippocampus” [94]. Another article [88] investigated the effect of intra-cerebroventricular injection of Ab fragments (Ab15-25, Ab25-35 and reverse sequenced Ab35-25) on synaptic transmission and LTP in the CA1 region of the hippocampus in vivo. This report [88] showed an impairment of LTP in a time- (for Ab25-35) and concentration-dependent manner (for Ab25-35 and Ab35-25) but left open the question (as did another recent study, Ref. 90) what would be the effect of Ab1-40 or Ab1-42 in such experimental condition. The authors suggested that injection of Ab1-40 at a dose of 300 pmol/day (the volume of injection, however, remained unclear) for 10-11 days impaired the hippocampal LTP [88]. Another earlier article [89] recorded waveforms in in vitro hippocampal slices at 250C (and not at standard 320C) after the injection of Ab1-40, and expressed LTP as a population spike (PS, but not EPSP) change versus time. Similarly, LTP was expressed as PS change versus time in early article on Ab oligomers [74]. Another earlier report showed no evidence of Ab1-40 accumulation or neurotoxicity after the injection of the peptide into rat hippocampus [91].

Recent behavioral study reported increase of the synaptic b-amyloid precursor protein with learning capacity in rats [53]. Behavioral analyses were characterized by both the absence and the presence of Ab effect on learning and memory in different behavioral experiments [91, 92, 93].

Several reports further addressed the puzzling issue of the role of Ab structural properties for neural function. These reports showed that oligomeric [73, 74, 76] and plaque [8, 95, 96, 97] amyloid is capable to impair synaptic or behavioral plasticity, possibly due to breaking the neuronal microcircuitry (see Ref. 8 for discussion details). All cited above studies of oligomeric Ab (also see [98]), while concluding on Ab neurotoxicity, however, miss consideration of the physiological association of Ab with lipoproteins, that potently arrests the peptide toxicity [70, 71, 72]. Such lack of important experimental consideration creates critical flaw of the Ab oligomers studies [73, 74, 76] and must warn all of a well possible lack of the pathophysiological relevance of Ab oligomers [98, 68]. Another recent study suggested age-related impairment of synaptic transmission (but not synaptic plasticity) in transgenic mice that overexpress human APP possessing “Swedish” mutation [99]. Such observation, however, unlikely contradicts the cited above four studies on the role of mature amyloid deposits [8, 95, 96, 97] due to the experimental differences (particularly, the lack of estimation of Ab load at the site of the recording, and employed for recording the stimulus intensity of 20 percent of experimental maximum).

At present it is impossible to unite cited above in vitro and in vivo electrophysiological and behavioral studies and conclude on the relevance of their experimental conditions to brain physiology and Alzheimer’s disease. The same is true for several most recent articles aiming to clarify the receptor machinery and signalling cascades involved in Ab-mediated modulation of synaptic plasticity [100, 101, 102, 103, 104]. For this reason in the present report we focused on a different (from the above listed studies) experimental condition that we previously characterized with regard to cholesterol and phospholipid metabolism status [3, 5].

It is also important to make a note that the majority of articles concluding on Ab as bad molecule oversight critical studies by others on an essential role for Ab in brain neurochemistry and the peptide beneficial effect on synaptic plasticity.

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