In Alzheimer's disease (AD), the first significant damage to neurons may be the loss of proteins involved in long-term potentiation (LTP) and memory. So conclude Dave Morgan and colleagues from the University of South Florida, Tampa, and Incyte Genomics, Palo Alto, California, in the June 15 Journal of Neuroscience.

First author Chad Dickey and colleagues used a combination of microarray and quantitative PCR (polymerase chain reaction) analysis to measure mRNA changes in a mouse model of AD. Amyloid precursor protein + presenilin-1 (APP + PS1) transgenic mice mimic the progress of the disease in that they deposit amyloid in the brain and suffer from age-related memory loss. When the authors compared these transgenic animals with normal mice, they found that genes involved in either LTP or memory, such as Homer-1a, are significantly downregulated in the TG mice. Importantly, this reduction in transcript levels was only found in areas of the brain where amyloid is deposited. In fact, of over 10,000 genes tested by microarray, only five were found to be downregulated in amyloid-rich brain samples, three (Arc, Zif268, and Nur77/TR3) being essential for memory and two (Na KATPase III and calsyntenin) being associated with synaptic activity. These losses seem to precede neuronal loss because Dickey and colleagues found that the levels of mRNAs coding for presynaptic proteins, including synapsin, synaptophysin and synaptotagmin, were unchanged.

In addition, the authors found that several genes associated with the inflammatory response, including glial fibrillary acid protein and proteins of the complement system, were upregulated in the transgenic mice. Though this effect was not restricted to amyloid burdened sections of the brain, it was in these samples where the increases were greatest. For example, complement component 4 was increased almost threefold in amyloid-laden tissue, but only about 1.8-fold in amyloid-free tissue.

The authors also extended their observations to human AD samples taken postmortem. In these samples, the same genes were downregulated as in the mice, but unlike in the latter, postsynaptic protein transcripts were also reduced, suggesting that the losses were due to loss of neurons.

Overall, the data suggest that LTP and memory effects precede the loss of neurons in the mouse model, which may accurately reflect the progression of the disease in humans. The data also support recent observations from the Selkoe lab that amyloid-β can significantly impair long-term potentiation when injected into the hippocampus (see ARF related news story).-Tom Fagan.

Dickey CA, Loring JF, Montgomery J, Gordon MN, Eastman PS, Morgan D. Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J. Neurosci. 2003 June 15;23:5219-5226. Abstract


Make a Comment

To make a comment you must login or register.

Comments on this content

  1. The header rather than the data come as a surprise, given the fact that APP(V717I) transgenic mice display a robust defect in LTP as well as in cognition (water maze) as early as age three to four months. This is in essence the most "early" phenotype of the APP Tg mice (Moechars et al., 1999) preceding by at least six months any neuropathology or amyloid deposits that become apparent at 10-12 months (Schneider et al., 2001; Dewachter et al., 2002). The present work provides the AD commmunity with a surprisingly short list of genes to analyse, which might contain the molecular players that "occupy early bases."

    Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van Leuven F. 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. Abstract

    Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N, Kuiperi C, Gilis M, Geerts H, Kretzschmar H, Godaux E, Moechars D, Van Leuven F, Herms J. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem. 2001 Apr 13;276(15):11539-44. Epub 2001 Jan 23. Abstract

    Dewachter I, Reverse D, Caluwaerts N, Ris L, Kuiperi C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. 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. Abstract

Comments on Primary Papers for this Article

No Available Comments on Primary Papers for this Article


News Citations

  1. Earliest Amyloid Aggregates Fingered As Culprits, Disrupt Synapse Function in Rats

Other Citations

  1. Abstract

Further Reading


  1. . Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J Neurosci. 2003 Jun 15;23(12):5219-26. PubMed.

Primary Papers

  1. . Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J Neurosci. 2003 Jun 15;23(12):5219-26. PubMed.