P1‐109: Mitochondrial Dysfunction Induced by a Posttranslationally Modified Amyloid Linked to a Familial Mutation in an Alternative Model of Neurodegeneration

Abstract

Familial British dementia (FBD) is an early-onset non-amyloid-β (Aβ) cerebral amyloidosis that presents with severe cognitive decline and strikingly similar neuropathological features to those present in Alzheimer's disease (AD). FBD is associated with a T to A single nucleotide transition in the stop codon of a gene encoding BRI2, leading to the production of an elongated precursor protein. Furin-like proteolytic processing at its C-terminus releases a longer-than-normal 34 amino acid peptide, ABri, exhibiting amyloidogenic properties not seen in its 23 amino acid physiologic counterpart Bri1-23. Deposited ABri exhibits abundant post-translational pyroglutamate (pE) formation at the N-terminus, a feature seen in truncated forms of Aβ found in AD deposits, and coexists with neurofibrillary tangles almost identical to those found in AD. We tested the impact of the FBD mutation alone and in conjunction with the pE post-translational modification on the structural properties and associated neurotoxicity of the ABri peptide. The presence of pE conferred to the ABri molecule enhanced hydrophobicity and accelerated aggregation/fibrillization properties. ABri pE was capable of triggering oxidative stress, loss of mitochondrial membrane potential and activation of caspase-mediated apoptotic mechanisms in neuronal cells, whereas homologous peptides lacking the elongated C-terminus and/or the N-terminal pE were unable to induce similar detrimental cellular pathways. The data indicate that the presence of N-terminal pE is not in itself sufficient to induce pathogenic changes in the physiologic Bri1-23 peptide but that its combination with the ABri mutation is critical for the molecular pathogenesis of FBD.

Ion channel formation by N-terminally truncated Aβ (4–42): relevance for the pathogenesis of Alzheimer's disease

“…It is now clear that the conformational transition from soluble to fibrillar material is a highly complex process modulated by a variety of factors, among them the presence of post translational modifications in the Aβ molecule including N-and C-terminal truncations as studied in the current work. The interlinked cellular pathways compromised by Aβ -many of them shared by those elicited by non-Aβ oligomeric conformations associated with other forms of cerebral amyloidosis [36,54] -are currently under active investigation. Among the most studied pathways, induction of apoptotic/cell death mechanisms, oxidative stress, metabolic/mitochondrial dysfunction, and the ability of amyloid subunits to assemble into functional ion channel-like structures in lipidic environments are the most relevant [55,56].…”

“…In contrast, Aβ 4-34 , bearing an additional C-terminal truncation display a primarily random conformation in the experimental timeframe. Thioflavin T binding, largely associated with the presence of cross β-sheet structures and typically correlating with the existence of fibrillar and/or protofibrillar components [36], also varied between both peptides. In accordance with its tendency to form β-sheet structures, Aβ 4-42 exhibited much higher fluorescence values than the freshly solubilized peptide after 2h incubation (Figure 1C).…”