Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Aβ APP mutation

Abstract

Pathogenic amyloid-β peptide precursor (APP) mutations clustered around position 693 of APP—position 22 of the Aβ sequence—are commonly associated with congophilic amyloid angiopathy (CAA) and intracerebral hemorrhages. In contrast, the Osaka (E693Δ) intra-Aβ APP mutation shows a recessive pattern of inheritance that leads to AD-like dementia despite low brain amyloid on in vivo positron emission tomography imaging. Here, we investigated the effects of the Osaka APP mutation on Aβ accumulation and deposition in vivo using a newly generated APP transgenic mouse model (E22ΔAβ) expressing the Osaka mutation together with the Swedish (K670N/M671L) double mutation. E22ΔAβ mice exhibited reduced α-processing of APP and early accumulation of intraneuronal fibrillar Aβ oligomers associated with cognitive deficits. In line with our in vitro findings that recombinant E22Δ-mutated Aβ peptides form amyloid fibrils, aged E22ΔAβ mice showed extracellular CAA deposits in leptomeningeal cerebellar and cortical vessels. In vitro results from thioflavin T aggregation assays with recombinant Aβ peptides revealed a yet unknown antiamyloidogenic property of the E693Δ mutation in the heterozygous state and an inhibitory effect of E22Δ Aβ42 on E22Δ Aβ40 fibrillogenesis. Moreover, E22Δ Aβ42 showed a unique aggregation kinetics lacking exponential fibril growth and poor seeding effects on wild-type Aβ aggregation. These results provide a possible explanation for the recessive trait of inheritance of the Osaka APP mutation and the apparent lack of amyloid deposition in E693Δ mutation carriers.

Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight

“…In AD, Ab peptides of 40 and 42 amino acids acquire a b-sheet structure, which is proaggregator and leads to the formation of dimers, oligomers, insoluble fibers, and NP formation [96,97]. Oligomers represent the most toxic aggregation stage of Ab, because they promote excitotoxicity by interacting with glutamate receptors, endoplasmic reticulum stress, mitochondrial dysfunction, altered acetyl-cholinergic neurotransmission, inflammation, and oxidative stress [98].…”

Animal Models of Vascular Cognitive Impairment and Dementia (VCID)

“…However, thioflavin T aggregation assays using recombinant Ab showed an antiamyloidogenic property of the mutation in the heterozygous state, in addition to an inhibitory effect of E22D Ab 42 on E22D Ab 40 fibrillogenesis. E22D Ab 42 has unique aggregation kinetics, which lack exponential fibril growth and have poor seeding effects on WT Ab aggregation (Kulic et al 2012).…”

Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques

“…Many of the accumulating immunoreactive molecules appear to be APP and/or fragments of APP rather than Aß (Winton, Lee et al 2011). This could represent the accumulation of normal APP and its metabolites, however the intracellular amyloid in at least two mouse models also reacts with conformation dependent antibodies that recognize pathologically misfolded oligomeric and fibrillar amyloid (Oddo, Caccamo et al 2006; Ferretti, Partridge et al 2011; Kulic, McAfoose et al 2012). Increasing evidence indicates that amyloids are structurally diverse and conformation dependent antibodies can detect these structural differences by the exposure or hiding of their epitopes depending on the particular aggregation state (Kayed, Head et al 2003; Kayed, Head et al 2007; Glabe 2008; Kayed, Pensalfini et al 2009).…”