In the field’s current focus to understand what might go wrong at synapses early on in AD, measuring long-term potentiation has become a widely applied tool. This phenomenon of synaptic strengthening in response to intense stimulation via NMDA receptors is thought to underlie learning and memory. The jury on that question is still out, but LTP and related measurements have become widely accepted as a sensitive method of characterizing changes in synaptic function. Consequently, a growing number of labs have imported this technique into their study of AD mouse models.

Natasha Shinsky and colleagues at Elan Pharmaceuticals in South San Francisco yesterday presented a technical twist on this approach by using a microelectrode array developed by a German company to record simultaneously from 60 channels placed all over the mouse hippocampus. While this does not in itself improve the information one receives from each recorded field, the simultaneous data gathered from multiple points can be analyzed to better understand the response from the whole system rather than from just the one spot surrounding the recording electrode.

Shinksy, with Karen Chen and others, studied PDAPP mice at two time points: at five to seven months, when they have not deposited plaques yet, and at 18 to 20 months, when plaques litter the mice’s brains. Much previous work on mice models has focused on neuronal loss (i.e., its absence) and degeneration. Recent work, in Lennart Mucke’s, Frank LaFerla’s, and Dominic Walsh’s labs, for example, hints at LTP changes prior to plaque deposition. Yet, it is not clear how that relates to cognitive deficits (see, for example, Dewachter et al., 2002).

Shinksy measured basic synaptic transmission, paired-pulse ratio, and LTP induced in two different ways. Slices of five-month-old mice showed significant impairment in only one of these measures, namely LTP induced with high-frequency stimulation. The old mice showed alterations in all parameters measured. Taken together, this suggests that PDAPP mice have problems controlling transmitter release, probably develop internal calcium overload as a result of disturbed calcium homeostasis, have abnormal inhibition by the neurotransmitter GABA, and fewer synaptic sites than nontransgenic mice, the authors propose.—Gabrielle Strobel

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. With regard to the above story by Gabrielle Strobel (very good, as always!), we want to comment on the following paragraph:

    "Recent work, in Lennart Mucke’s, Frank LaFerla’s, and Dominic Walsh’s labs, for example, hints [italics mine] at LTP changes prior to plaque deposition. Yet, it is not clear how that relates to cognitive deficits (see, for example Dewachter et al., 2002)."

    We appreciate the citation of our recent work in the conditional knockout PS1(n-/-) mice (Dewachter et al., 2002), but we must draw your readers’ attention to the fact that we described already in 1999 (and not before a heroic fight with several editors and referees from several journals) an "early phenotype" including defective LTP and defective cognition (water-maze) in young APP mice, i.e., at three to six months, which is six months before any plaques are evident! The relevant reference is:

    Moechars et al., 1999 "Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain (see Fig. 5)."

    Our data did somewhat more than "hint" at defective LTP prior to and independent of amyloid plaque formation; they actually proved in 1999 (data were acquired in 1997-98) that amyloid plaques are not essential for an array of symptoms in the early disease process in our transgenic mouse model for the amyloid pathology in AD!

    We have now several (published) arguments for this fact:

    (i) defects in behaviour of mice that overexpress mouse APP, which does not give rise to amyloid plaques (Moechars et al., 1996);

    (ii) defects in cognition in mice that overexpress human wild-type APP695 that also do not develop plaques (Moechars et al., 1999, ibid.);

    (iii) the combination of APP[V717I] x PS1(n-/-) mice that do not develop plaques, but are at a young age already cognitive impaired (Dewachter et al., 2002, ibid.).

    We remain convinced that the "separation in time of the first phase(s) of disease from amyloid deposition"—i.e., the early and late phases of the phenotype—is thereby well and truly established in the model. Our APP[V717I] transgenic mice are an excellent transgenic model for all aspects of amyloid deposition "at old age," i.e., amyloid plaques in brain parenchym followed by vascular amyloid deposition and angiopathy (Van Dorpe et al., 2000). This progressive deposition is certainly not "healthy" for the brain and triggers immunochemical reactions and scavenging activity, thereby increasing the "turning of the vicious circle." Still, those are the "late" phases of the phenotype, most comparable to the late clinical phases in AD patients.

    We have provided sound arguments and believe that there is actually no reason not to extrapolate these findings from the transgenic model to the human AD patient, inferring that not amyloid peptide deposition but amyloid peptides inside the neurons are to be reckoned with as the prime and early pathological actors. We have stated this most clearly and explicitly, and continue to do so, since we—and all of us, I believe—want nothing more than to either prevent AD or at least stop it in its most early phases—for us the only humane way to treat AD. We would, then, argue to refer to the most early phases of the amyloid cascade as "neuronal amyloid peptide"—NAP—without implying any particular physical form of the peptide, but thereby bring the evident amyloid lesion somewhat closer to that other equally evident pathological lesion in AD, the neurofibrillary tangles, or NFT. Whether NAP or NFT are first or second—or coplayers—in the human disease is subject for an other debate!

    References:

    . Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1;22(9):3445-53. PubMed.

    . Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999 Mar 5;274(10):6483-92. PubMed.

    . Expression in brain of amyloid precursor protein mutated in the alpha-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice. EMBO J. 1996 Mar 15;15(6):1265-74. PubMed.

    . Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons. Am J Pathol. 2000 Oct;157(4):1283-98. PubMed.

References

News Citations

  1. Synapses Sizzle in Limelight of Symposium Preceding Neuroscience Conference, Orlando: Day 2
  2. Earliest Amyloid Aggregates Fingered As Culprits, Disrupt Synapse Function in Rats

Paper Citations

  1. . Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1;22(9):3445-53. PubMed.

Other Citations

  1. Lennart Mucke’s

Further Reading

No Available Further Reading