Why pleiotropic interventions are needed for Alzheimer's disease

Abstract

Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of beta-amyloid (Abeta) peptide aggregates or aberrant amyloid precursor protein (APP) processing. Much is known of the factors initiating the disease process decades prior to the onset of cognitive deficits, but an unclear understanding of events immediately preceding and precipitating cognitive decline is a major factor limiting the rapid development of adequate prevention and treatment strategies. Multiple pathways are known to contribute to cognitive deficits by disruption of neuronal signal transduction pathways involved in memory. These pathways are altered by aberrant signaling, inflammation, oxidative damage, tau pathology, neuron loss, and synapse loss. We need to develop stage-specific interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Abeta production and accumulation, and oxidative damage), but also address damage from these pathways that will not be reversed by targeting prodromal pathways. This approach would not only focus on blocking early events in pathogenesis, but also adequately correct for loss of synapses, substrates for neuroprotective pathways (e.g., docosahexaenoic acid), defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting). Monotherapy targeting early single steps in this complicated cascade may explain disappointments in trials with agents inhibiting production, clearance, or aggregation of the initiating Abeta peptide or its aggregates. Both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions during the "prodromal" period prior to conversion to "mild cognitive impairment (MCI)." Furthermore, many of the pathological events are no longer proceeding in series, but are going on in parallel. By the MCI stage, we stand a greater chance of success by considering pleiotropic drugs or cocktails that can independently limit the parallel steps of the AD cascade at all stages, but that do not completely inhibit the constitutive normal functions of these pathways. Based on this hypothesis, efforts in our laboratories have focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin in multiple models that cover many steps of the AD pathogenic cascade (Cole and Frautschy, Alzheimers Dement 2:284-286, 2006).

Figures

Fig. 1

Stage-dependent pathogenesis: This figure illustrates the complexity of different pathogenic events (inflammation, synaptic loss, oxidative damage in addition to imaging, and CSF biomarkers) at different stages, showing that there is extensive tau and Aβ pathology prior to symptoms. Identifying plasma or CSF biomarkers specific for targeted pathway (inflammation, neurodegeneration) is important for the rapid development of treatments and early interventions

Fig. 2

Hypothetical Alzheimer cascade: Argument for pleiotropic targeting. This schematic diagram illustrates a refinement of the amyloid cascade, suggesting that more than one pathogenic pathway contributes to memory loss and demonstrating how anti-Aβ or other monotherapies would not succeed on their own. Examples of such pathogenic pathways that need to be targeted are oxidative damage (which depletes membrane n-3 fatty acids like DHA), aberrant inflammation, and pTau accumulation. In agreement with the “baptists,” Aβ accumulation is a triggering event. But in agreement with the “taoists,” both tau aggregates and increased pTau are likely to be major contributors to memory deficits (even though tangle pathology is not specific to AD). Nevertheless, reducing tau aggregation is unlikely to be sufficient since other events including impaired energy metabolism and aberrant are contributing to memory deficits. Compounds like curcumin or DHA or both are likely to be effective in targeting multiple steps