Aberrant interactions between amyloid-beta and alpha5 laminins as possible driver of neuronal disfunction in Alzheimer's disease

• It has been widely accepted that laminins are involved in pathogenesis of Alzheimer's disease (AD). Amyloid plaques in AD patients are associated with immunostaining using antibodies raised against laminin-111, and laminin-111 has been shown to prevent aggregation of amyloid peptides. Although numerous articles describe small peptides from laminin-111 that are capable to disaggregate amyloid buildups and reduce neurotoxicity in in vitro and in vivo models, there is no approved laminin-111-based therapeutic approaches for treatment of AD. Also, it has been shown that immunoreactivity to laminin111 appears late in development of cerebral amyloidosis. Based on the published data, we hypothesize that aberrant interaction between amyloid-beta and alpha 5-laminins such as laminin-511 prevents the necessary laminin signaling into neurons leading to neurodegeneration and contributing to the early development of AD. Laminin-511 is the key extracellular protein that protects neurons from anoikis, inhibits excitoxicity and provides signaling that stabilizes dendritic spines and synapses in the developed brain. Absence of the signaling from laminin-511 leads to behavioral defects in mice. Laminin-511 and hippocampal neurons are in direct contact and accumulation of amyloid-beta that has been shown to avidly bind laminin-511 may physically decouple the interaction between alpha 5-laminins and the neuronal membrane receptors inhibiting the signaling. Under this hypothesis, protein domains and peptides from laminin alpha 5 chain may have a therapeutic potential in treatment of AD and the appearance of laminin-111 in the amyloid plaques is simply a consequence of the disease.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

Laminins

Amyloid-beta

Neurodegeneration

Alzheimer's disease

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