Clinico-pathologic function of cerebral ABC transporters - implications for the pathogenesis of Alzheimer's disease

Abstract

In recent years it has become evident that ABC transporters fulfill important barrier functions in normal organs and during disease processes. Most importantly, resistance to drugs in cancer cells led to intense oncological and pharmacological investigations in which researchers were able to highlight important pharmacological interactions of chemotherapeuticals with ABC transporter function. Recently, the development of neurodegenerative diseases and the maintenance of neuronal stem cells have been linked to the activity of ABC transporters. Here, we summarize findings from cell culture experiments, animal models and studies of patients with Alzheimer's disease. Furthermore, we discuss pharmacological interactions and computational methods for risk assessment.

Fig. (1)

ABC transporters at the blood-brain barrier. Top: Schematic drawing of a brain capillary. The BBB is comprised essentially of the endothelial cells (E), the basal membrane (BM), and astrocytic processes (AP). Pericytes (not shown) also contribute to the cellular barrier. The cerebral endothelial cells are connected via tight junctions (TJ). Bottom: Localization of ABC transporters at the brain capillary endothelial cells. Transporters localized in either the luminal (apical) or basolateral part of the cell membrane restrict uptake (apical) or excretion (basolateral) of drugs and toxic metabolic products. P-gp – P-glycoprotein, MRP – multidrug resistance protein, BCRP – breast cancer resistance protein. Based on data from [2, 9, 12, 59, 96].

Fig. (2)

Accumulation Aβ-immunoreactive material (antibody clone 4G8) in a 175 day-old Mdr1a/b-deficient mouse (B) expressing the Dutch-type variant of APP. Large pyramidal neurons in layer 5 (D – cortex & F – layer 5) and neurons in CA1-3 of the hippocampal formation (E) show small, Aβ-positive endolysosomes. Control DTAPP-type mice (A), which are not deficient for Mdr1a/b, do not show intracellular deposits (C – CA1 of hippocampal formation). Scale bars: A, B and D: 500μm; E: 100μm; C and F: 50μm.

Fig. (3)

Schematic model for the mathematical evaluation of clearance, degradation, and aggregation of Aβ involving ABC transporters at the BBB. Aβ aggregates into oligomers, protofibrils and fibrils. The kinetics of aggregation and disaggregation vary, thus the timepoints of plaque development and the onset of neurotoxic effects are highly dependent on these factors. The aggregates and monomers can be degraded by different proteases. Additionally, Aβ monomers and small Aβ multimers are transported by BBB transporters. The excretion capacity and its velocity are dependent on the charge, size and conformation of the Aβ peptides. Charge changes as known from Dutch-Aβ (E22Q) lead to hampered transport. After several months, the restricted clearance of Dutch-Aβ results in deposition at the BBB. Intracerebral toxic levels of metabolites and peptide oligomers impair the normal function of neurons and disturb the maintenance of NSPCs. Importantly, long-term inhibition of the ABC transporter excretion function at the BBB by therapeuticals (e.g. statins and beta-blockers) could put the patients at higher risk for developing neurodegenerative diseases. The knowledge of clearance, degradation, aggregation and excretion kinetics as well as the amount of a defined Aβ moiety needed to exert toxicity for specific neuronal or stem cell populations and its clinical outcome, can be used to calculate individual risk profiles.