The Amyloid .BETA. Protein Precursor Mutations Linked to Familial Alzheimer's Disease Alter Processing in a Way That Fosters Amyloid Deposition.

Younkin, Steven G.

doi:10.1620/tjem.174.217

Cited by 18 publications

(9 citation statements)

References 19 publications

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“…These results suggest that during ageing the cleavage of APP by γ‐secretase may shift to generate more Aβ42 than Aβ43, which in turn may lead to increased accumulation of Aβ42 in the brain. Several studies have shown that Aβ42 is more closely associated with AD pathogenesis than is Aβ40 [24–27]. The age‐related increase of Aβ42 observed in the present study supports these previous findings and is consistent with the hypothesis that increased Aβ42 generation or accumulation may promote, or even cause, sporadic AD pathogenesis in the aged brain.…”

Section: Discussionsupporting

confidence: 92%

Age‐related changes of intracellular Aβ in cynomolgus monkey brains

Kimura

Yanagisawa

Terao

et al. 2005

Neuropathology Appl Neurobio

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To confirm the intracellular accumulation of amyloid beta-protein (Abeta), we carefully performed immunohistochemistry using brains of cynomolgus monkeys of various ages. Cortical neurones and their large neurites were immunostained with antibodies against Abeta in young monkey brains. In aged monkey brains, intracellular Abeta localized within cortical neurones; no clear association was found between the presence of intracellular Abeta and senile plaques (SPs). Interestingly, we did not observe Abeta-immunoreactive cortical neurones in brains fixed with neutral buffered formalin. Western blot analyses of microsomal and nerve ending fractions derived from the brains of young to aged monkeys revealed that intracellular Abeta generation changed with age. In the microsomal fraction, the amount of Abeta42 significantly increased in brains from older monkeys (>30 years of age), and the amount of Abeta43 significantly decreased with age in the microsomal fraction. The amount of Abeta40 remained the same regardless of age. Biochemical analyses also showed that intracellular levels of each of these Abeta molecules significantly increased with age in nerve ending fractions. As we previously observed that a similar accumulation of presenilin1, beta-amyloid precursor protein (APP) and APP C-terminal fragment cleaved by beta-secretase in the nerve ending fractions obtained from brains with SPs, the accumulation of intracellular Abeta in this fraction may be closely related to formation of spontaneous SPs with age. Taken together, these results suggest that intensive investigation of age-related changes in the nerve ending will contribute to a better understanding of the pathogenesis of age-related neurodegenerative disorders such as sporadic Alzheimer's disease.

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Section: Discussionsupporting

confidence: 92%

Age‐related changes of intracellular Aβ in cynomolgus monkey brains

Kimura

Yanagisawa

Terao

et al. 2005

Neuropathology Appl Neurobio

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“…Many studies have shown that astrocytes are affected by soluble neuronal factors and several inflammationassociated cytokines (Eddleston and Mucke, 1993;Mark et al, 1995;McGeer and McGeer, 1995) and by Aβ (LaDu et al, 2001;Smits et al, 2002;Deb et al, 2003). Aβ40, the Aβ species thought to be the primary form of Aβ found in normal brain (Haas et al, 1992;Seubert et al, 1992;Shoji et al, 1992;Busciglio et al, 1993;VigoPelfrey et al, 1993), is less toxic than Aβ42 (Burdick et al, 1992;Jarrett et al, 1993;Suzuki et al, 1994;Younkin, 1994).…”

Section: Discussionmentioning

confidence: 99%

Aβ Upregulates and Colocalizes with LGI3 in Cultured Rat Astrocytes

et al. 2007

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1. The leucine-rich glioma inactivated (LGI) family of genes encodes a leucine-rich repeat (LRR) protein, proteins that are thought to be specifically involved in protein-protein and protein-matrix interactions. Since amyloid beta peptide (Abeta) has been previously shown to induce the expression of another LRR-encoding gene in neural cells, we assessed how Abeta affects LGI gene expression in rat primary cerebral cortical cultures and astrocyte cultures. Both RT-PCR and Western Blotting analyses revealed that Abeta robustly induced the expression of LGI3 in rat astrocyte cultures.2. Western Blotting analyses also showed that both glial fibrillary acidic protein (GFAP) and apolipoprotein E (ApoE) significantly increased coincidentally with the Abeta-induced upregulation of LGI3. Immunocytochemistry showed that LGI3 colocalized with Abeta at plasma membranes and also with internalized Abeta in astrocytes. These findings suggest that activated LGI3 may be involved in the astroglial response against Abeta.

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“…Mutations in the genes for APP, presenilin1 (PS1) and presenilin2 (PS2) that cause early-onset familial Alzheimer's disease (FAD) drive the processing of APP toward the amyloidgenic pathway, leading to an overproduction of Aβ (Scheuner, et al, 1996,Younkin, 1994). Moreover, the inheritable FAD mutations preferentially increase the 42 amino acid species of Aβ (Aβ42) that is considered the most toxic variant of Aβ (Hutton, et al, 1998,Sisodia, 1999,Younkin, 1998).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying basal and learning-related intrinsic excitability in a mouse model of Alzheimer's disease

Kaczorowski

Sametsky

Shah

et al. 2011

Neurobiology of Aging

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Accumulations of β-amyloid (Aβ) contribute to neurological deficits associated with Alzheimer's disease (AD). The effects of Aβ on basal neuronal excitability and learning-related AHP plasticity were examined using whole-cell recordings from hippocampal neurons in the 5XFAD mouse model of AD. A robust increase in Aβ42 (and elevated levels of Aβ38-40) in naïve 5XFAD mice was associated with decreased basal neuronal excitability, evidenced by a select increase in Ca2+-sensitive afterhyperpolarization (AHP). Moreover, trace fear deficits observed in a subset of 5XFAD weak-learner mice were associated with a greater enhancement of the AHP in neurons, as compared to age-matched 5XFAD learner and 5XFAD naïve mice. Importantly, learning-related plasticity of the AHP remained intact in a subset of 5XFAD mice that learned trace fear conditioning to a set criterion. We show that APP-PS1 mutations enhance Aβ and disrupt basal excitability via a Ca2+-dependent enhancement of the AHP, and suggest disruption to learning-related modulation of intrinsic excitability resulted, in part, from altered cholinergic modulation of the AHP in the 5XFAD mouse model of AD.

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The Amyloid .BETA. Protein Precursor Mutations Linked to Familial Alzheimer's Disease Alter Processing in a Way That Fosters Amyloid Deposition.

Cited by 18 publications

References 19 publications

Age‐related changes of intracellular Aβ in cynomolgus monkey brains

Age‐related changes of intracellular Aβ in cynomolgus monkey brains

Aβ Upregulates and Colocalizes with LGI3 in Cultured Rat Astrocytes

Mechanisms underlying basal and learning-related intrinsic excitability in a mouse model of Alzheimer's disease

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