The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-? peptides (A?), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different A? peptides existing are generated by subsequent cleavage of the amyloid-? protein precursor (A?PP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species A?40 and A?42, A? peptides with other C-termini such as A?38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against A?38 to analyze the distribution of this A? species in cases of sporadic and familial AD, as well as in the brains of a series of established transgenic AD mouse models. We found A?38 to be present as vascular deposits in the brains of the majority of sporadic AD cases, whereas it is largely absent in non-demented control cases. A?38-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed A?38-positive plaques not only among familial cases due to A?PP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that A?38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only A?PP, or combinations of A?PP, PSEN1, and tau transgenes.
Abnormalities and impairments in axonal transport are suggested to strongly contribute to the pathological alterations underlying AD. The exact mechanisms leading to axonopathy are currently unclear, but it was recently suggested that APP expression itself triggers axonal degeneration. We used APP transgenic mice and crossed them on a hemi- or homozygous PS1 knock-in background (APP/PS1KI). Depending on the mutant PS1 dosage, we demonstrate a clear aggravation in both plaque-associated and plaque-distant axonal degeneration, despite of an unchanged APP expression level. Amyloid-? (A?) peptides were found to accumulate in axonal swellings as well as in axons and apical dendrites proximate to neurons accumulating intraneuronal A? in their cell bodies. This suggests that A? can be transported within neurites thereby contributing to axonal deficits. In addition, diffuse extracellular A? deposits were observed in the close vicinity of axonal spheroids accumulating intracellular A?, which might be indicative of a local A? release from sites of axonal damage.
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