Neocortical Synapse Density and Braak Stage in the Lewy Body Variant of Alzheimer Disease: A Comparison with Classic Alzheimer Disease and Normal Aging

Brown, Daniel F.; Risser, Richard C.; Bigio, Eileen H.; Tripp, Patrick; Stiegler, Ashley; Welch, Erin; Eagan, Kathleen P.; Hladik, Christa L.; White, Charles L.

doi:10.1097/00005072-199810000-00007

Cited by 63 publications

(30 citation statements)

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“…It has also been validated previously by comparisons with quantitative immunoblots Mucke et al, 1994), quantitations of synaptic proteins by ELISA (Brown et al, 1998;Buttini et al, 1999), and the optical "disector" approach (Masliah et al, 1991a;Everall et al, 1999;Hsia et al, 1999). To ensure objective assessments and reliability of results, brain sections from mice to be compared in any given experiment were blind coded and processed in parallel.…”

Section: Methodsmentioning

confidence: 99%

High-Level Neuronal Expression of Aβ_1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

et al. 2000

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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 A␤ peptides. The platelet-derived growth factor ␤ chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral A␤ 1-42 levels, whereas an experimental mutation of the ␤-secretase cleavage site (671 M3I ) eliminated production of human A␤.High levels of A␤ 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 A␤ levels but not with hAPP levels or plaque load. We conclude that A␤ is synaptotoxic even in the absence of plaques and that high levels of A␤ 1-42 are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent A␤ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

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Section: Methodsmentioning

confidence: 99%

High-Level Neuronal Expression of Aβ_1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

et al. 2000

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“…This semiquantitative assessment of neurodegenerative alterations (see Materials and Methods for details) has been used successfully in diverse experimental models 3,24,32 and in diseased human brains. 22,33,34 It has also been validated previously by comparisons with quantitative immunoblots, 35 quantitations of synaptic proteins by enzymelinked immunosorbent assay, 32,36 and modifications of the stereological "disector" approach. 37 Compared with hAPP Ϫ/Ϫ SR ϩ/ϩ controls, hAPP Ϫ/Ϫ SR Ϫ/Ϫ mice had normal levels of synaptophysin-immunoreactive presynaptic terminals (Figure 5), suggesting that lack of the SR does not by itself result in abnormal central nervous system (CNS) development or neurodegenerative alterations.…”

Section: Lack Of the Sr Does Not Affect Extent Of Neurodegeneration Imentioning

confidence: 99%

Elimination of the Class A Scavenger Receptor Does Not Affect Amyloid Plaque Formation or Neurodegeneration in Transgenic Mice Expressing Human Amyloid Protein Precursors

Huang

Buttini

Wyss‐Coray

et al. 1999

The American Journal of Pathology

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“…S ynaptic perturbations are strongly linked to cognitive decline and memory impairment in patients with early-stage Alzheimer's disease (AD) (1,2). The accumulation of soluble oligomeric clusters of amyloid-β (Aβ), a secreted proteolytic derivative of the amyloid precursor protein (APP), may be important for the early synaptic failure that is seen in AD pathogenesis (3)(4)(5)(6).…”

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confidence: 99%

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

Reinders

Pao

Renner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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Amyloid-β (Aβ) is a prime suspect for causing cognitive deficits during the early phases of Alzheimer’s disease (AD). Experiments in AD mouse models have shown that soluble oligomeric clusters of Aβ degrade synapses and impair memory formation. We show that all Aβ-driven effects measured in these mice depend on AMPA receptor (AMPAR) subunit GluA3. Hippocampal neurons that lack GluA3 were resistant against Aβ-mediated synaptic depression and spine loss. In addition, Aβ oligomers blocked long-term synaptic potentiation only in neurons that expressed GluA3. Furthermore, although Aβ-overproducing mice showed significant memory impairment, memories in GluA3-deficient congenics remained unaffected. These experiments indicate that the presence of GluA3-containing AMPARs is critical for Aβ-mediated synaptic and cognitive deficits.

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Neocortical Synapse Density and Braak Stage in the Lewy Body Variant of Alzheimer Disease: A Comparison with Classic Alzheimer Disease and Normal Aging

Cited by 63 publications

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High-Level Neuronal Expression of Aβ_1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

High-Level Neuronal Expression of Aβ_1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

Elimination of the Class A Scavenger Receptor Does Not Affect Amyloid Plaque Formation or Neurodegeneration in Transgenic Mice Expressing Human Amyloid Protein Precursors

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

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Neocortical Synapse Density and Braak Stage in the Lewy Body Variant of Alzheimer Disease: A Comparison with Classic Alzheimer Disease and Normal Aging

Cited by 63 publications

References 0 publications

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

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

Elimination of the Class A Scavenger Receptor Does Not Affect Amyloid Plaque Formation or Neurodegeneration in Transgenic Mice Expressing Human Amyloid Protein Precursors

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

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Resources

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High-Level Neuronal Expression of Aβ_1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

High-Level Neuronal Expression of Aβ_1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation