Intraneuronal amyloid β and reduced brain volume in a novel APP T714I mouse model for Alzheimerʹs disease

Transgenic mouse models of Alzheimerʹs disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated Aβ42 in absence of Aβ40. In vitro, this mutation leads to one of the highest Aβ42/Aβ40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal Aβ in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal Aβ deposits colocalized with late endosomal markers, although some Aβ inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of Aβ accumulation in the endosomal–lysosomal pathway and the hypothesis that intraneuronal accumulation of Aβ could be an important factor in the AD pathogenesis.