hasemmodels.blogg.se

Design-based stereology method for counting organelles
Design-based stereology method for counting organelles










design-based stereology method for counting organelles

discovered that soluble oligomers are common to amyloids, like the Aβ peptide in AD and demonstrated that the soluble amyloid oligomers tested display a common conformation-dependent structure unique to soluble oligomers regardless of the primary sequence. have led to the proposal that before fibrillisation, natively unstructured monomeric Aβ is subject to large conformational changes involving predominantly β-sheet type structures. Solid-state nuclear magnetic resonance and electron microscopy studies by Chimon et al. The authors used electron microscopy and atomic force microscopy to show that dimerisation and subsequent monomer addition are processes in which significant and asymmetric monomer conformational changes occur. reported that Aβ monomers are unstructured, but oligomers exhibit order-dependent increases in β-sheet content. Dimeric oligomers extracted from AD brain impaired synaptic structure and function.

design-based stereology method for counting organelles

The most toxic forms of Aβ assemblies are soluble oligomers rather than fibrillary assemblies. The “amyloid cascade hypothesis” claims that assemblies of monomeric Aβ initiate a process leading to neuron dysfunction, neuron death and dementia. Passive immunisation with TAP01, a murine antibody directed against the N-terminus of AβpE3-42 has beneficial effects in preclinical AD mouse models. N-truncated Aβ species are highly abundant in AD brain, are toxic and induce synaptic dysfunction. A number of major variants of extracellular Aβ have been identified, including full-length Aβ1-42, Aβ1-40, Aβ4-42 and a form with an N-terminal pyroglutamate (pE, pGlu) Aβ3-42 (AβpE3-42). Growing evidence suggests that soluble forms of Aβ are key to AD progression and may represent attractive therapeutic targets as they inhibit long-term potentiation, trigger synaptic plasticity and synapse loss. While amyloid plaques represent typical hallmarks of AD, soluble oligomers have been shown to better correlate with the clinical pathology. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aβ, which offers new routes for active and passive immunisation against AD.Īlzheimer’s disease (AD) is a progressive neurodegenerative condition characterised by the presence of extracellular deposits of the amyloid-beta (Aβ) protein.

design-based stereology method for counting organelles

Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. We engineered a stabilised cyclic form of Aβ1-14 (N-Truncated Amyloid Peptide AntibodieS the ‘TAPAS’ vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aβ3-14, we identified a novel pseudo β-hairpin structure in the N-terminal region of Aβ and show that this underpins its unique binding properties. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aβ species. The Aβ peptide exists in several forms, including full-length Aβ1-42 and Aβ1-40 – and the N-truncated species, pyroglutamate Aβ3-42 and Aβ4-42, which appear to play a major role in neurodegeneration. One of the hallmarks of Alzheimer’s disease (AD) are deposits of amyloid-beta (Aβ) protein in amyloid plaques in the brain.












Design-based stereology method for counting organelles