A Systems Approach to Drug Discovery in Alzheimer's Disease

Abstract

In the articles included in this volume, one feels a strong frustration among the writers with the slow course of therapeutics development for Alzheimer's disease and with the clinical failure of targeted therapeutic agents despite substantial progress in our understanding of the biology and biochemistry of the disease. Keywords Master regulator . Interactome . Human neuronsTo date, approaches to Alzheimer disease (AD) therapeutics have followed 2 main avenues. The first addresses neurotransmitter deficits in the early phases of the disease. This approach has led to the handful of AD drugs currently on the market that provide short-term symptomatic improvement but do not alter the course of the disease. The second approach has been directed at decreasing the burden of beta-amyloid (Aβ) in the brain by active or passive immunization or by inhibiting activity of β-or γ-secretases. To date, none of the approaches in this second class has been successful, although trials on β-or γ-secretase (BACE) inhibitors are ongoing.The lack of overt success has been even more frustrating because, in transgenic (Aβ-overproducing) mouse models of AD, Aβ-lowering approaches, as well as treatments with small molecules and biologics, have been successful in blocking memory loss, restoring memory function, reversing dendritic spine alterations, and reversing inhibition of longterm potentiation [1][2][3]. Indeed, as animal models only partially recapitulate the human AD phenotype and because human brain tissue is available only postmortem, translation of preclinical findings to the clinics has been fraught with difficulties.For instance, the characteristic intraneuronal neurofibrillary tangles and extensive neuronal loss observed in human AD are absent in mouse models of the disease. This dichotomy suggests that mouse models replicate only presymptomatic AD stages, while clinical manifestations appear only after neuronal loss becomes irreversible. This hypothesis is directly addressed by ongoing trials, where individuals with genetic mutations that predispose to early AD onset are being treated with Aβ-targeted therapies to assess whether presymptomatic treatment may block an otherwise certain disease progression. Beyond Aβ-targeted therapies, novel approaches are being developed based on inhibition of tau phosphorylation and aggregation, and on blockade of synaptic loss, leveraging "candidate" target approaches derived from human and animal data. Unfortunately, it has so far been impossible to discern whether "candidate genes" represent causal determinants of the disease process or are the downstream result of them.In this review, we will discuss the potential of adapting integrative systems biology approaches that have already proven extremely valuable in understanding multiple cancer related phenotypes to human neurodegenerative diseases.

The recurrent architecture of tumour initiation, progression and drug sensitivity

“…More specifically, these results support the idea of a human-to-mouse-to-human (H2M2H) methodology 31,93 , in which preclinical models are optimally matched to human tumours based on the statistical significance of their tumour checkpoint MR overlap. This would increase the probability of results from preclinical studies using these models being relevant to human disease.…”

The Coming of Age of the Angiotensin Hypothesis in Alzheimer’s Disease: Progress Toward Disease Prevention and Treatment?

“…What continues to be a major stumbling block is the determination of the correct chronology of factors and events that give rise to AD and how these interact at a systems level to explain the progression of the disease and all the neuropathological and clinical nuances that are characteristically seen. The progress thus far provides significant hope for the potential gains to be had from wider adoption of integrative systems biology approaches, that have made substantial contributions to the progress of cancer research, to the study of AD [ 24 ]. A wider perspective of the various contributory processes in the pathogenesis of AD is more likely to allow new lines of drug discovery [ 24 ], or prompt the reconsideration of the drugs already known and used for other conditions that could be repurposed to have greater benefit in timely studies for the prevention of treatment of AD [ 25 ].…”

Master Regulators of Infiltrate Recruitment in Autoimmune Disease Identified through Network-Based Molecular Deconvolution

“…Systems-level analysis using reverse-engineered regulatory networks is an emerging computational discipline that has demonstrated great promise in the study of complex diseases such as cancer and Alzheimer’s disease (Aubry et al, 2015; Chen et al, 2014; Shelanski et al, 2015; Zhang et al, 2013). This approach enables the modeling of complex physiological behaviors as modules of genes (subsets of differentially expressed genes that associate with disease) that are controlled by master regulators (MRs).…”

“…behaviors of a tumor mass. Physiological behaviors such mesenchymal transformation in glioblastoma (Carro et al, 2010) and oncogenesis in B cell lymphoma or breast cancer (Chen et al, 2014; Mani et al, 2008), as well as onset of Alzheimer’s disease(Zhang et al, 2013) have been functionally linked to a relatively small number of MRs, which in turn become the “bottleneck” that can be used to infer driver mutations in patients(Chen et al, 2014) or become the targets of drug screens for treatment(Shelanski et al, 2015). …”