Webster, Marie-Therese; (1996) Studies on the amyloid precursor protein: Implications for Alzheimer's disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

It is believed that the progressive accumulation and deposition of beta-amyloid peptide (β/A4) in Alzheimer's disease (AD), results from one or several errors in the normal metabolism of its precursor, amyloid precursor protein (APP). Using antibody 22C11 raised to the N-terminus of APP, amyloid precursor protein-like immunoreactivity (APPLIR) was determined by Western blotting in a soluble and two membrane fractions of human brain. Species of APPLIR present were characterised using antibodies 7H5, 10D5 and DA1 which recognise motifs of APP other than the N-terminal sequence. Total soluble APPLIR was found to be higher in AD, which may reflect reduced non-amyloidogenic α-secretory processing of APP. Given that choline acetyltransferase activity was also lower in AD when comparing the same samples, this result may be related to cholinergic hypoactivity. Multiple regression analysis, used to investigate correlations of cortical cell parameters with APPLIR concentrations, indicated that pyramidal neurones may represent the major source of APP in brain and that secretory APP processing possibly depends on cortical pyramidal neurone activity. Furthermore, measurements of secreted APPLIR concentration in ventricular cerebrospinal fluid of patients receiving lithium, hypothesised to attenuate the signal transduction cascade linking receptor activation to secretory processing of APP, and those drugs capable of reducing cortical excitatory transmission e.g. anticholinergic drugs, were found to be reduced. When comparing human brain enzyme preparations thought to contain the candidate β/A4-generating protease β-secretase, enzyme activity was found to be lower in AD temporal cortex when compared to controls. Thus alternative, potentially amyloidogenic pathways may be favoured in AD e.g. the endosomes/lysosomes. In energy perturbed PC 12 cells, observations following treatment with the lysosomotropic agent chloroquine suggested that endosomal/lysosomal processing of APP may be favoured with sparing of secretory cleavage. Finally, the first monoclonal antibody (3B11) to the APP homologue, amyloid precursor-like protein 2 (APLP2) was prepared and characterised. Observations suggested that APLP2 may be abundant in brain membranes, which may highlight an important role for this non-amyloidogenic species. Development of 3B11 makes it possible to examine APLP2 in preparations containing APP. In conclusion, there appears to be a relationship between cortical pyramidal neurone hypoactivity, cholinergic pathology and reduced non-amyloidogenic processing of APP. Lowered rates of β-secretase cleavage of APP may also be a feature of AD. Mechanism(s) favouring mismetabolism of APP are unknown. However, perturbed energy metabolism may be implicated. Possible therapeutic interventions based on pharmacological approaches being developed for AD (e.g. enhancing cholinergic transmission) have been suggested to beneficially affect the metabolism of APP by favouring α-secretory processing which cannot lead to β/A4 deposition.

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