BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals

Why Pleiotropic Interventions are Needed for Alzheimer's Disease

Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of β-amyloid (Aβ) 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, Aβ 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 Aβ 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)

Thymic maturation and programmed cell death

The thymus plays a crucial role in the development and maintenance of the immune system, being the main site of T cell differentiation and maturation throughout life. Associated to dramatic structural changes, its function seems to markedly diminish with time, never the less, there are several data indicating that, despite organ atrophy, at least part of the thymus remains active throughout one's lifetime. In the last decades, several studies, aiming to understand the significance of age-dependent changes in thymic structure and function, highlighted the concept that developmental and maturational stages strongly depend on the balanced and coordinated occurrence of life and death options. In particular, programmed cell death represents a fundamental requirement in order to assure a proper functionality of the immune response and to avoid the formation of uncontrolled and potentially self-damaging lymphocytic clones. By contrast, the time-dependent thymic atrophy is due to progressive replacing of lymphoid with adipose tissue. In the light of the increased knowledge on the factors/mechanisms controlling the process of adipogenesis, it could be suggested that fat accumulation in the thymic stroma might not be considered a passive, deleterious consequence of aging, but instead a potential source of molecules with various biological functions. Therefore, thymus represents a very interesting model in terms of energy expenditure and trade off, tissue homeostasis, immune defence and disease escape. The implications of changes in thymic structure, in the ratio of proliferation and programmed cell death as well as the occurrence of fat involution still represent an open question and will be discussed in the present chapter