Self-Propagative Replication of Aβ Oligomers Suggests Potential Transmissibility in Alzheimer Disease

Abstract

The aggregation of amyloid-β (Aβ) peptide and its deposition in parts of the brain form the central processes in the etiology of Alzheimer disease (AD). The low-molecular weight oligomers of Aβ aggregates (2 to 30 mers) are known to be the primary neurotoxic agents whose mechanisms of cellular toxicity and synaptic dysfunction have received substantial attention in the recent years. However, how these toxic agents proliferate and induce widespread amyloid deposition throughout the brain, and what mechanism is involved in the amplification and propagation of toxic oligomer species, are far from clear. Emerging evidence based on transgenic mice models indicates a transmissible nature of Aβ aggregates and implicates a prion-like mechanism of oligomer propagation, which manifests as the dissemination and proliferation of Aβ toxicity. Despite accumulating evidence in support of a transmissible nature of Aβ aggregates, a clear, molecular-level understanding of this intriguing mechanism is lacking. Recently, we reported the characterization of unique replicating oligomers of Aβ42 (12–24 mers) in vitro called Large Fatty Acid-derived Oligomers (LFAOs) (Kumar et al., 2012, J. Biol. Chem). In the current report, we establish that LFAOs possess physiological activity by activating NF-κB in human neuroblastoma cells, and determine the experimental parameters that control the efficiency of LFAO replication by self-propagation. These findings constitute the first detailed report on monomer – oligomer lateral propagation reactions that may constitute potential mechanism governing transmissibility among Aβ oligomers. These data support the previous reports on transmissible mechanisms observed in transgenic animal models.

Conformational Dynamics of Specific Aβ Oligomers Govern Their Ability To Replicate and Induce Neuronal Apoptosis

“…This observation is in good agreement with our previous report on LFAO replication. 15 As LFAO seed concentration increased from 0.5 to 3 μM, the fold increase (replication efficiency) decreased from 6.1 to 2.6 (Table 1). However, increasing the LFAO seed concentration to 10 and 14 μM resulted in insignificant replication efficiency of 1.7 and 1.5, respectively (Figure 1F, Table 1).…”

“…21–23 However, this data does support our previous observation that LFAOs could be immuno-detected by the conformation-specific OC antibody, indicative of the fibril-like nature of LFAOs. 15 …”

“…Immunoblots of increasing concentrations of LFAOs revealed that the larger molecular weight distribution (80–110 kDa) increases as LFAO concentration increases from 0.5 to 10 μM (Figure 4A), as observed previously. 14,15 At 0.5 μM, LFAOs are primarily 12mers (single arrow), with negligible 24mer band (double arrow). However, increasing the LFAO concentration to 10 μM reveals a more disperse oligomer, comprised of 12 and 24mer LFAOs.…”

“…15 In the same report, the propensity of LFAOs to form oligomers of two disperse molecular weight ranges upon replication was established. These results lead to the question of whether concentration-dependent conformational and aggregation dynamics of LFAOs could be responsible for the observed inverse correlation between concentration and replication efficiency.…”

Structural differences between amyloid beta oligomers

“…Oligomeric forms of Aβ peptides are highly neurotoxic, are believed to play an important causal role in the AD pathogenesis and their levels correlate strongly with AD progression [3,4]. Amyloid oligomers have also been shown to play an important role in the cell to cell transmission of AD pathology due to their ability to penetrate cellular membranes [5][6][7].…”