Axonal degeneration in an Alzheimer mouse model is PS1 gene dose dependent and linked to intraneuronal Aß accumulation.

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-ß (Aß) peptides were found to accumulate in axonal swellings as well as in axons and apical dendrites proximate to neurons accumulating intraneuronal Aß in their cell bodies. This suggests that Aß can be transported within neurites thereby contributing to axonal deficits. In addition, diffuse extracellular Aß deposits were observed in the close vicinity of axonal spheroids accumulating intracellular Aß, which might be indicative of a local Aß release from sites of axonal damage.

Aß38 in the brains of patients with sporadic and familial Alzheimer's disease and transgenic mouse models.

The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-ß peptides (Aß), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aß peptides existing are generated by subsequent cleavage of the amyloid-ß protein precursor (AßPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aß40 and Aß42, Aß peptides with other C-termini such as Aß38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against Aß38 to analyze the distribution of this Aß 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 Aß38 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. Aß38-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aß38-positive plaques not only among familial cases due to AßPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aß38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AßPP, or combinations of AßPP, PSEN1, and tau transgenes.