High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation
By L. Mucke, E. Masliah, Gui-qiu Yu, M. Mallory, E. Rockenstein, G. Tatsuno, K. Hu, D. Kholodenko, K. Johnson-wood, L. McConlogue. Journal of Neuroscience, 2000
1,924 citations recorded by the source corpus.
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 Aβ1–42 levels, whereas an experimental mutation of the β-secretase cleavage site (671M→I) eliminated production of human Aβ. High levels of Aβ1–42 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 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.
Subfields: Cell Biology, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/a32a3fb1056eea1e5591a2e00dd0e2ebb2813590
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Citations in the corpus
- Soluble oligomers of amyloid β-protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake (2009, neutral): “In accord, impairment of synaptic plasticity can be detected in vivo before the formation of insoluble Ab deposits in APP transgenic mouse models (e.g., Hsia et al., 1999; Mucke et al., 2000 ).”
- Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers (2004, background): “Such impairment of synaptic plasticity may account for plaque-independent cognitive failures seen in hAPP transgenic mice (Hsia et al., 1999; Mucke et al., 2000; Buttini et al., 2002; Van Dam et al., 2003), which accumulate oligomers in an age-, region-, and transgenedependent manner (Chang et al.”
- Alzheimer's disease. (2011, background): “transgenic for human APP (either without or with human PS1 coexpression) have been generated (Games et al. 1995; Hsiao et al. 1996; Holcomb et al. 1998; Mucke et al. 2000; Oddo et al. 2003).”
- Complement and Microglia Mediate Early Synapse Loss in Alzheimer Mouse Models (2016, neutral): “S4), long before Aβ plaques deposit (11, 12), raising the question of whether C1q increase in these pre-plaque brains is dependent on soluble Aβ levels.”
- Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model (2010, methodology): “In our published studies, wtAPP mice are known to produce much lower amounts of Aβ (28) and to have normal spatial learning and memory as compared with those mAPP/ABAD mice that had higher levels of Aβ and revealed significant impairments in spatial memory (51).”
- APP mouse models for Alzheimer's disease preclinical studies (2017, neutral): “APP overexpression for instance might induce behavioral abnormalities prior to A b pathology (Hsiao et al , 1996; Mucke et al , 2000), as A b pathology arises much earlier than overt disease onset in humans.”
- Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. (2007, neutral): “…Indiana FAD mutations; line ARC48 expresses hAPP carrying the Swedish, Indiana, and Arctic FAD mutations; line I5 expresses wild-type hAPP; and line N8 overexpresses wild-type mouse Fyn (Cheng et al., 2004; Chin et al., 2004, 2005; Dawson et al., 2001; Mucke et al., 2000; Roberson et al., 2007).”
- Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: The emerging role of oligomeric assemblies (2002, neutral): “Subsequently, monitoring of a variety of neurophysiological measures revealed that significant neuronal injury occurred before the appearance of plaques (Dodart et al., 1999; Hsia et al., 1999; Larson et al., 1999; Moechars et al., 1999; Kumar-Singh et al., 2000; Mucke et al., 2000).”
- Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease (2005, methodology): “Mucke were used in these studies because of their considerable previous characterization (30).”
- Conformational constraints for amyloid fibrillation: the importance of being unfolded. (2004, result): “Several recent investigations lend support to the idea that fibrillar proteins (as in senile plaques in AD or Lewy bodies in PD) are not necessarily the toxic entity, but rather the formation of some ‘‘protofibrillar’’ structures is responsible for the toxicity [57–61].”
- Folding proteins in fatal ways (2003, background): “Comparisons of transgenic lines with different APP expression levels suggest that these decreases in presynaptic terminals are dependent on Aβ concentrations, not on the Aβ plaque burde”