Assembly Blocker Program

In 1998, Acumen’s founders were first to describe ADDLs and document the potent neurotoxicity of these assemblies (Lambert et al, 1998).  ADDLs block long term potentiation (LTP) a form of neuronal plasticity that is widely studied as a paradigm for learning and memory (Wang et al, 2002), and brain slice culture experiments demonstrated that selective ADDLs toxicity to hippocampal neurons compared with cerebellar neurons corresponded to AD pathology (Kim et al, 2002).  ADDLs have been shown to be 70-fold higher in AD brain tissue extracts compared to extracts for age-matched control tissues (Gong et al, 2003).  ADDL selective antibodies have been shown to reverse ADDL-induced neurotoxicity and block the binding of ADDLs to neurons (Lambert et al, 2001).  Very recent experiments revealed highly specific ADDL binding to synaptic receptors, providing the first demonstration that ADDLs directly interfere with synaptic function (Lacor et al, 2004).  ADDL binding leads to rapid and persistent up-regulation of arc, a key gene associated LTP induction (Steward et al, 1998; Guzowski et al, 2000).  Finally, recent studies have shown that antibodies capable of binding ADDLs reverse memory deficits when injected into the brains of transgenic mice over-expressing human Aβ42 (Dodart et al, 2003; Kotilinek et al, 2002), and active vaccination with oligomer containing preparations of Ab42 prevents age-dependent onset of memory failure (Morgan et al, 2000).

The fibril/plaque paradox inherent in the classical amyloid cascade hypothesis is readily reconciled by Ab42 aggregation to form ADDLs, and that cognitive deficits emanate from synaptic disruption by ADDLs rather than neuronal death due to plaques and fibrils.  The ADDL hypothesis provides a consistent explanation for the earliest subtle cognitive deficits of mild cognitive impairment (MCI) triggered by aberrant neuron signaling due to low concentrations of ADDLs, and the more severe deficits and progressive, degenerative cellular pathology of AD caused by persistent attack of high concentration of ADDLs.  ADDLs are now widely believed to be the primary cause of AD, and a significant contributor to related cognitive disorders such as MCI and Down’s syndrome (Klein, 2000; Walsh et al, 2002; Xia et al, 1997; Kirkitadze et al, 2002; El-Agnaf et al, 2000; Huang et al, 2000; Sian et al,2000).