Profiling the culprit in Alzheimer's disease (AD): bacterial toxic proteins - Will they be significant for the aetio-pathogenesis of AD and the transmissible spongiform encephalopathies?
The aetiology of Alzheimer's disease (AD) and the transmissible spongiform encephalopathies (tSEs) is still elusive. The concept that prion protein (PrP(Sc)) is the aetiological agent (infectious protein) in the tSEs has recently been questioned. In AD, the cause of the aberrant cleavage of the beta-amyloid precursor protein (APP), resulting in the production of amyloidogenic Abeta fragments, has yet remained obscure. Moreover, the amyloid hypothesis of AD has been seriously challenged. In both AD and the tSEs, pathogens of various nature, including bacteria, have been discussed as possible causal factors. However, aetiological considerations have completely neglected microbial products such as the bacterial toxic proteins (BTPs). The present paper is aimed at drawing a "culprit profile" of these toxic molecules that can exert, at low-dosage, neuro-degeneration through various effects. Clearly, BTPs may affect cell-surface receptors including modulatory amine transmitter receptor expression, block neuro-transmitter release, increase intra-cellular Ca(2+) levels, affect intra-cellular signal transduction, change cyto-skeletal processing, alter synaptic transmission, influence APP proteolysis, interact with cell surface proteins like PrP(C) or their GPI anchors, act as chaperones inducing conformational change in proteins (e.g., PrP(C) to PrP(Sc)), alter lipid membrane integrity by affecting phospholipases or forming pores and channels, induce vacuolar (spongiform) change and elicit inflammatory reactions with cytokine production including cytokines that were demonstrated in the AD brain. Like PrP(Sc), BTPs can be heat-stable and acid-resistant. BTPs can meet the key-proteins of AD and tSEs in the lipid-rich domains of the plasma membrane called rafts. Basically, this might enable them to initiate a large variety of unfavourable molecular events, eventually resulting in pathogenetic cascades as in AD and the tSEs. All in all, their profile lends support to the hypothesis that BTPs might represent relevant culprits capable to cue and/or promote neuro-degeneration in both AD and the tSEs.
Schmitt
H Peter
HP
Institute of Pathology, Department for Neuropathology, University of Heidelberg, Germany. horst.schmitt@med.uni-heidelberg.de
D000544:Alzheimer Disease / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry; D020134:Catalytic Domain; D016207:Cytokines / Q000378:metabolism; D004777:Environment; D005690:Galactose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008954:Models, Biological; D018377:Neurotransmitter Agents / Q000378:metabolism; D017096:Prion Diseases / Q000276:immunology* / Q000628:therapy*; D011328:Prions / Q000737:chemistry; D017510:Protein Folding
D016564:Amyloid beta-Protein Precursor; D001427:Bacterial Toxins; D016207:Cytokines; D018377:Neurotransmitter Agents; D011328:Prions; D005690:Galactose