The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ

Kalimo, Hannu; Łałowski, Maciej; Bogdanović, Nenad; Philipson, Ola; Bird, Thomas D.; Nochlin, David; Schellenberg, Gerard D.; Brundin, RoseMarie; Olofsson, Tommie; Soliymani, Rabah; Baumann, Marc; Wirths, Oliver; Bayer, Thomas A.; Nilsson, Lars; Basun, Hans; Lannfelt, Lars; Ingelsson, Martin

doi:10.1186/2051-5960-1-60

Cited by 40 publications

(36 citation statements)

References 52 publications

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“…The therapeutic potential of oligomer-specific monoclonal antibodies for AD therapeutics has led to development of humanized forms. An antibody described as targeting protofibrillar AβOs, promoted by the Arctic mutation [74], reduced AβOs in the brains and CSF of the mouse model with no impact on Aβ monomers [169]. The humanized version (BAN2401) has obtained favorable safety profile in Phase 1 clinical trials.…”

Section: Therapeuticsmentioning

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: Therapeuticsmentioning

confidence: 99%

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

2015

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“…Aβ in the amyloid state is virtually always present in AD, but an instructive exception is a rare hereditary type of AD caused by a mutation that changes glutamate to glycine at position 22 of Aβ (E22G; the ‘arctic’ mutation). This mutation results in early-onset AD in which Aβ plaques lack the prototypical amyloid cores (Kalimo et al, 2013), indicating that ‘amyloid’ in the strict sense is not required to drive the Aβ-cascade. Similarly, even though misfolded prion protein (PrP) has an enhanced ability to form amyloid, PrP-amyloid per se is not obligatory for the expression of prion disease (DeArmond and Prusiner, 1995).…”

Section: The Neuropathology Of Ad In the Context Of The Prion Paradigmmentioning

confidence: 99%

Prion-like mechanisms in Alzheimer disease

Walker

2018

Handbook of Clinical Neurology

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Senile plaques and neurofibrillary tangles are the principal histopathologic hallmarks of Alzheimer disease. The essential constituents of these lesions are structurally abnormal variants of normally generated proteins: Aβ protein in plaques and tau protein in tangles. At the molecular level, both proteins in a pathogenic state share key properties with classic prions, i.e., they consist of alternatively folded, β-sheet-rich forms of the proteins that autopropagate by the seeded corruption and self-assembly of like proteins. Other similarities with prions include the ability to manifest as polymorphic and polyfunctional strains, resistance to chemical and enzymatic destruction, and the ability to spread within the brain and from the periphery to the brain. In Alzheimer disease, current evidence indicates that the pathogenic cascade follows from the endogenous, sequential corruption of Aβ and then tau. Therapeutic options include reducing the production or multimerization of the proteins, uncoupling the Aβ-tauopathy connection, or promoting the inactivation or removal of anomalous assemblies from the brain. Although aberrant Aβ appears to be the prime mover of Alzheimer disease pathogenesis, once set in motion by Aβ, the prion-like propagation of tauopathy may proceed independently of Aβ; if so, Aβ might be solely targeted as an early preventive measure, but optimal treatment of Alzheimer disease at later stages of the cascade could require intervention in both pathways.

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“…The Arctic mutation in APP (E693G) occurs within the sequence of Aβ (E22G), causes enhanced Aβ protofibril formation, produces distinct fibril morphology, and results in a distinct AD pathology (27)(28)(29)(30). In contrast, the Swedish mutation (K670M/N671L) occurs outside the Aβ sequence but results in the overproduction of WT Aβ and typical AD pathology (31)(32)(33).…”

Section: Significancementioning

confidence: 99%

Serial propagation of distinct strains of Aβ prions from Alzheimer’s disease patients

Watts

Condello

Stöhr

et al. 2014

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

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228

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An increasing number of studies argues that self-propagating protein conformations (i.e., prions) feature in the pathogenesis of several common neurodegenerative diseases. Mounting evidence contends that aggregates of the amyloid-β (Aβ) peptide become self-propagating in Alzheimer's disease (AD) patients. An important characteristic of prions is their ability to replicate distinct strains, the biological information for which is enciphered within different conformations of protein aggregates. To investigate whether distinct strains of Aβ prions can be discerned in AD patients, we performed transmission studies in susceptible transgenic mice using brain homogenates from sporadic or heritable (Arctic and Swedish) AD cases. Mice inoculated with the Arctic AD sample exhibited a pathology that could be distinguished from mice inoculated with the Swedish or sporadic AD samples, which was judged by differential accumulation of Aβ isoforms and the morphology of cerebrovascular Aβ deposition. Unlike Swedish ADor sporadic AD-inoculated animals, Arctic AD-inoculated mice, like Arctic AD patients, displayed a prominent Aβ38-containing cerebral amyloid angiopathy. The divergent transmission behavior of the Arctic AD sample compared with the Swedish and sporadic AD samples was maintained during second passage in mice, showing that Aβ strains are serially transmissible. We conclude that at least two distinct strains of Aβ prions can be discerned in the brains of AD patients and that strain fidelity was preserved on serial passage in mice. Our results provide a potential explanation for the clinical and pathological heterogeneity observed in AD patients.neurodegeneration | bioluminescence imaging | seeding | proteinopathies

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The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ

Cited by 40 publications

References 52 publications

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

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

Prion-like mechanisms in Alzheimer disease

Serial propagation of distinct strains of Aβ prions from Alzheimer’s disease patients

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