Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

Bartl, Jasmin; Meyer, Andrea; Riederer, Peter; Grünblatt, Edna

doi:10.1007/s00702-012-0852-5

Cited by 15 publications

(8 citation statements)

References 37 publications

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“…3). Furthermore, when insulin receptors are down, GSK3β activity is up, and this may be germane to pTau elevation [4]. Decreased CNS insulin signaling which appears to occur with age could tip the scales toward AβOs in the struggle for synaptic survival.…”

Section: Introductionmentioning

confidence: 99%

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

2015

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Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson’s and Alzheimer’s. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer’s dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca2+ overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

2015

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“…Remarkably, consistent datasets lacked amyloid β (A4) precursor protein APP. One possible explanation is that differential expression of APP monomer is negligible, while its pathological role unfolds at the level of toxic oligomers [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Knowledge-based compact disease models identify new molecular players contributing to early-stage Alzheimer’s disease

Mayburd

Baranova

2013

BMC Systems Biology

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BackgroundHigh-throughput profiling of human tissues typically yield as results the gene lists comprised of a mix of relevant molecular entities with multiple false positives that obstruct the translation of such results into mechanistic hypotheses. From general probabilistic considerations, gene lists distilled for the mechanistically relevant components can be far more useful for subsequent experimental design or data interpretation.ResultsThe input candidate gene lists were processed into different tiers of evidence consistency established by enrichment analysis across subsets of the same experiments and across different experiments and platforms. The cut-offs were established empirically through ontological and semantic enrichment; resultant shortened gene list was re-expanded by Ingenuity Pathway Assistant tool. The resulting sub-networks provided the basis for generating mechanistic hypotheses that were partially validated by literature search. This approach differs from previous consistency-based studies in that the cut-off on the Receiver Operating Characteristic of the true-false separation process is optimized by flexible selection of the consistency building procedure. The gene list distilled by this analytic technique and its network representation were termed Compact Disease Model (CDM). Here we present the CDM signature for the study of early-stage Alzheimer’s disease. The integrated analysis of this gene signature allowed us to identify the protein traffic vesicles as prominent players in the pathogenesis of Alzheimer’s. Considering the distances and complexity of protein trafficking in neurons, it is plausible that spontaneous protein misfolding along with a shortage of growth stimulation result in neurodegeneration. Several potentially overlapping scenarios of early-stage Alzheimer pathogenesis have been discussed, with an emphasis on the protective effects of AT-1 mediated antihypertensive response on cytoskeleton remodeling, along with neuronal activation of oncogenes, luteinizing hormone signaling and insulin-related growth regulation, forming a pleiotropic model of its early stages. Alignment with emerging literature confirmed many predictions derived from early-stage Alzheimer’s disease’ CDM.ConclusionsA flexible approach for high-throughput data analysis, the Compact Disease Model generation, allows extraction of meaningful, mechanism-centered gene sets compatible with instant translation of the results into testable hypotheses.

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“…Perhaps this discrepancy reflects the use of aged Aβ peptides in that study 22 . Indeed, soluble versus aged/aggregated Aβ peptide has been shown to elicit distinct phenotypes in SH-Sy5y cells 46 . Table 1.…”

Section: Discussionmentioning

confidence: 99%

The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression

Quartey

Nyarko

Maley

et al. 2021

Sci Rep

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The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1–38), interacts with the AD-related variant, Aβ(1–42), and the predominant physiological variant, Aβ(1–40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1–38) interacts differently with Aβ(1–40) and Aβ(1–42) and, in general, Aβ(1–38) interferes with the conversion of Aβ(1–42) to a β-sheet-rich aggregate. Functionally, Aβ(1–38) reverses the negative impact of Aβ(1–42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1–42) phenotype in Caenorhabditis elegans. Aβ(1–38) also reverses any loss of MTT conversion induced by Aβ(1–40) and Aβ(1–42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1–38) and Aβ(1–42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1–42)/Aβ(1–38) [and Aβ(1–42)/Aβ(1–40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1–38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1–42).

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Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

Cited by 15 publications

References 37 publications

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

Knowledge-based compact disease models identify new molecular players contributing to early-stage Alzheimer’s disease

The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression

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