Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?

In the present review, we summarize the current achievements of modelling early intraneuronal A beta (amyloid beta-peptide) accumulation in transgenic mice with the resulting pathological consequences. Of special importance will be to discuss recent developments and the translation of the results to AD (Alzheimer's disease). N-terminally truncated A beta(pE3) (A beta starting with pyroglutamate at position 3) represents a major fraction of all A beta peptides in the brain of AD patients. Recently, we generated a novel mAb (monoclonal antibody), 9D5, that selectively recognizes oligomeric assemblies of A beta(pE3) and demonstrated the potential involvement of oligomeric A beta(pE3) in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost non-detectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal staining was observed. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall A beta levels and stabilized behavioural deficits. In summary, we have demonstrated that intraneuronal A beta is a valid risk factor in model systems and AD patients. This feature of AD pathology was successful in identifying novel low-molecular-mass oligomeric A beta-specific antibodies for diagnosis and therapy.