Home › Research › Disease mechanisms
High-Level Neuronal Expression of Aβ1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation
Lennart Mucke, Eliezer Masliah, Gui-Qiu Yu, Margaret E. Mallory, Edward M. Rockenstein, Gwen P. Tatsuno, Kang Hu, Dora Kholodenko, Kelly Johnson‐Wood, Lisa McConlogue. Journal of Neuroscience, 2000-06-01
Topic: Brain proteins, microglia and lab models
Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic Abeta peptides. The platelet-derived growth factor beta chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Abeta(1-42) levels, whereas an experimental mutation of the beta-secretase cleavage site (671(M-->I)) eliminated production of human Abeta. High levels of Abeta(1-42) resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Abeta levels but not with hAPP levels or plaque load. We conclude that Abeta is synaptotoxic even in the absence of plaques and that high levels of Abeta(1-42) are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Abeta toxicity plays an important role in the development of synaptic deficits in AD and related conditions.
Why it matters
In mice engineered to make human amyloid protein precursor, high levels of Aβ1-42 were linked to fewer presynaptic nerve terminals even in mice that formed no plaques. The authors conclude that amyloid-beta is synaptotoxic even in the absence of plaques.
How this study scored 55/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on strength of evidence, so that was left out: it earned 52 of the 95 points we could judge it on, which is 55 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Neuroscience) |
| Journal's citation record | 4 / 4 | Journal of Neuroscience: journal h-index 651 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | — / 5 | No evidence rating recorded — left out of this score |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2000 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “transgenic”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 7 / 7 | Cited 1,864 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 66.6 citations a year over 28 year(s) since 2000 |
| Impact for its field and year | 5 / 6 | Cited 27.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 3 / 4 | Cited 142 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Lisa McConlogue: h-index 36 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, San Francisco: institution h-index 1,915 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 10818140) |
| Free to read | 2 / 2 | Free to read |
| Points | 52 / 95 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 52 of the 95 points we could judge it on is 55 out of 100. |
| Total | 55 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1523/jneurosci.20-11-04050.2000
- PubMed: 10818140
- Original source →
- Free full text: Journal of Neuroscience →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 10 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Mucke, L., Masliah, E., Yu, G.-Q., Mallory, M. E., Rockenstein, E. M., Tatsuno, G. P., et al. (2000). High-Level Neuronal Expression of Aβ1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation. Journal of Neuroscience. https://doi.org/10.1523/jneurosci.20-11-04050.2000
Vancouver
Mucke L, Masliah E, Yu G.-Q, Mallory ME, Rockenstein EM, Tatsuno GP, et al. High-Level Neuronal Expression of Aβ1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation. Journal of Neuroscience. 2000. doi:10.1523/jneurosci.20-11-04050.2000. PMID: 10818140.
BibTeX
@article{mucke2000-10818140,
author = {Mucke, Lennart and Masliah, Eliezer and Yu, Gui-Qiu and Mallory, Margaret E. and Rockenstein, Edward M. and Tatsuno, Gwen P. and Hu, Kang and Kholodenko, Dora and Johnson‐Wood, Kelly and McConlogue, Lisa},
title = {{High-Level Neuronal Expression of Aβ1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation}},
journal = {Journal of Neuroscience},
year = {2000},
doi = {10.1523/jneurosci.20-11-04050.2000},
pmid = {10818140},
url = {https://doi.org/10.1523/jneurosci.20-11-04050.2000}
}
Related studies in Disease mechanisms
Also tagged “mice”
1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.