Consequences of Inhibiting Amyloid Precursor Protein Processing Enzymes on Synaptic Function and Plasticity

Wang, Hui; Megill, Andrea; He, Kaiwen; Kirkwood, Alfredo; Lee, Hey Kyoung

doi:10.1155/2012/272374

Cited by 38 publications

(30 citation statements)

References 292 publications

(336 reference statements)

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“…This is consistent with findings reported in AD mouse models overexpressing mutant forms of amyloid precursor protein (APP) (19,20; reviewed in ref. 21). The reduced transmission could be due to a reduced postsynaptic responsiveness or to a decreased probability of neurotransmitter release.…”

Section: Resultsmentioning

confidence: 99%

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Ardiles

Tapia-Rojas

Mandal

et al. 2012

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

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Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated. memory dysfunction | neural plasticity | aging | T-maze | hippocampus A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of abnormally processed proteins in neurofibrillary tangles (NFTs) and senile plaques (1). These lesions are present in both familial and sporadic forms of AD. Familial AD is linked to inherited mutations in AD-related genes and represents a small percentage of AD cases, whereas sporadic AD represents the vast majority of cases and is not inherited. Results from transgenic mice bearing mutations in APP, PSEN1/2, and TAU show synaptic dysfunction in early stages of AD, before overt neurodegeneration (2, 3). More recent studies have demonstrated a critical role for soluble Aβ oligomers as an early trigger for AD, as well as associations with memory and neural plasticity loss (4-8).Although transgenic mice have been extremely useful in elucidating the pathological mechanisms of AD, they have some substantial limitations. Examples include the absence of tau mutations linked to AD except for a triple transgenic mouse 3xTg-AD, bearing mutations for APP, PSEN1/2, and TAU (9); inability to develop the whole spectrum of the disease; overexpression of transgenes into a nonphysiological scenario; and the fact that the manipulated genes represent only familial, not sporadic forms of AD (10, 11). It would be highly desirable to have a nontransgenic model of AD to complement the existing models. Several species naturally develop features of AD with age; however, the usefulness of these species is limited, because none exhibits the full spectrum of AD-related alterations (12-14). For example, the Aβ peptide sequences of Cavia porcellus (guinea pig) and Microcebus murinus are similar to that of huma...

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Section: Resultsmentioning

confidence: 99%

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Ardiles

Tapia-Rojas

Mandal

et al. 2012

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

Self Cite

120

107

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“…β-secretase is one of important enzymes in the process of APP to Aβ42 (26). However, significant change in the β-secretase activity as measured BACE activity assays, suggests that β-secretase may not play a role in Aβ reduction caused by (−)epicatechin diet.…”

Section: Discussionmentioning

confidence: 99%

Effects of (âˆ’)Epicatechin on the Pathology of APP/PS1 Transgenic Mice

2014

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Background: Alzheimer’s disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The clearance of Aβ from the brain and anti-inflammation are potential important strategies to prevent and treat disease. In a previous study, we demonstrated the grape seed extract (GSE) could reduce brain Aβ burden and microglia activation, but which polyphenol plays a major role in these events is not known. Here, we tested pharmacological effects of (−)epicatechin, one principle polyphenol compound in GSE, on transgenic AD mice.Methods: APP/PS1 transgenic mice were fed with (−)epicatechin diet (40 mg/kg/day) and curcumin diet (47 mg/kg/day) at 3 months of age for 9 months, the function of liver, Aβ levels in the brain and serum, AD-type neuropathology, plasma levels of inflammatory cytokines were measured.Results: Toward the end of the experiment, we found long-term feeding of (−)epicatechin diet was well tolerated without fatality, changes in food consumption, body weight, or liver function. (−)Epicatechin significantly reduced total Aβ in brain and serum by 39 and 40%, respectively, compared with control diet. Microgliosis and astrocytosis in the brain of Alzheimer’s mice were also reduced by 38 and 35%, respectively. The (−)epicatechin diet did not alter learning and memory behaviors in AD mice.Conclusion: This study has provided evidence on the beneficial role of (−)epicatechin in ameliorating amyloid-induced AD-like pathology in AD mice, but the impact of (−)epicatechin on tau pathology is not clear, also the mechanism needs further research.

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“…These cytotoxic Aβ42 aggregates have been hypothesized to play a causative and central role in AD onset and progression. Potential therapeutic approaches to AD include reducing Aβ42 synthesis by targeting the enzymes that process amyloid precursor protein (APP) to Aβ42 [2][3][4], inhibiting Aβ42 aggregation [5,6], increasing the clearance of Aβ42 from the brain [7,8], decreasing Aβ42 aggregate burden in the brain [8,9], and reducing inflammation associated with Aβ42 deposition [10,11].…”

Section: Introductionmentioning

confidence: 99%

Functional Characteristics and Molecular Mechanism of a New scFv Antibody Against Aβ42 Oligomers and Immature Protofibrils

et al. 2014

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Amyloid β peptide (Aβ42) is a major determinant of Alzheimer's disease (AD). In this study, we studied a novel single-chain variable fragment (scFv), AS, generated from an antibody library of AD patients, which recognized and bound specifically to medium-size amyloid β peptide (Aβ42) oligomers and immature protofibrils (25-55 kDa) and, more importantly, reduced their level by blocking their formation or inducing their disassembly. Consequently, scFv AS ameliorated or prevented their cytotoxicity and protected SH-SY5Y cells and primary cultured neurons in vitro from their damage in a concentration-dependent manner. Comparison of its cytotoxicity-inhibiting and cytotoxicity-neutralizing activities indicated that scFv AS displayed its protective effect on target cells mainly due to its cytotoxicity-inhibitory activity though it could also neutralize the cytotoxicity. We also found that scFv AS could efficiently cross the in vitro BBB model with a delivery efficiency of over 70% after a 60-min post-administration. The scFv AS was a monovalent antibody with an affinity constant (KD) of 5.5 × 10(-6) M and a binding threshold of 6.25 × 10(-4) μM for Aβ42 oligomers. The molecular docking simulations of Aβ42 to scFv AS revealed that scFv AS tends to approached Aβ42 oligomers and immature protofibrils mainly by their hydrophobic interaction and then drew Aβ42 molecule into the gap between VL and VH domains of scFv AS by hydrophilic interaction between scFv AS and the N-terminal region (residues 1-15) of Aβ42 and the hydrophobic interactions between scFv AS and the middle region (residues 20-33) of Aβ42. The combination of scFv AS with Aβ42 was realized likely through an induced-fit process.

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Consequences of Inhibiting Amyloid Precursor Protein Processing Enzymes on Synaptic Function and Plasticity

Cited by 38 publications

References 292 publications

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Effects of (âˆ’)Epicatechin on the Pathology of APP/PS1 Transgenic Mice

Functional Characteristics and Molecular Mechanism of a New scFv Antibody Against Aβ42 Oligomers and Immature Protofibrils

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