High-Level Neuronal Expression of Aβ1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

Journal of Neuroscience - Tập 20 Số 11 - Trang 4050-4058 - 2000
Lennart Mucke1,2,3, Eliezer Masliah4, Gui-Qiu Yu2, Margaret Mallory4, Edward Rockenstein4, Gwen Tatsuno5, Kang Hu5, Dora Kholodenko5, Kelly Johnson-Wood5, Lisa McConlogue5
1Department of §§ Neurology and
2Gladstone Institute of Neurological Disease
3Neuroscience Program, University of California, San Francisco, California 94141-9100
4Departments of Neurosciences and Pathology, University of California at San Diego, La Jolla, California 92093-0624, and
5Elan Pharmaceuticals, South San Francisco, California 94080

Tóm tắt

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 Aβ peptides. The platelet-derived growth factor β chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Aβ1–42levels, whereas an experimental mutation of the β-secretase cleavage site (671M→I) eliminated production of human Aβ. High levels of Aβ1–42resulted 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 Aβ levels but not with hAPP levels or plaque load. We conclude that Aβ is synaptotoxic even in the absence of plaques and that high levels of Aβ1–42are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Aβ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

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Journal of Neuroscience

Tập 20 Số 11

4050-4058

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