Protein homeostasis as a therapeutical target for Alzheimer’s disease: analysis in the hippocampus of transgenic mouse models

Abstract

Alzheimer's disease (AD) constitutes the most prevalent form of dementia. There is no cure so there is an urgent need of novel therapeutic targets and treatments. The main histopathological hallmarks of AD brains are extracellular plaques formed by the beta-amyloid (Abeta) peptide, and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau (phospho-tau). In fact, AD is considered a neurodegenerative proteinopathy. The coexistence of these protein aggregates leads to synaptic damage, neuronal loss and cognitive decline in patients. The dysfunction of intracellular proteolytic systems (autophagy-lysosomal and ubiquitin-proteasome) has been postulated as a pathological mechanism contributing to the cerebral accumulation of these toxic proteins. Our aim is to verify the involvement of these pathways in the hippocampus of two different transgenic mice of AD to understand the differential impact of Abeta and phospho-tau accumulation on the pathological progression. Cerebral sections from APP/PS1 and ThyTau22 models (2 to 18 months) were analyzed. WT animals were used as controls. Immunohistochemical stainings were performed to evaluate amyloid deposition, phospho-tau accumulation, autophagic/lysosomal markers and ubiquitin at different pathological stages. In the amyloidogenic model we found a pathological accumulation of autophagic vesicles, lysosomes and ubiquitin in periplaque dystrophic neurites. In ThyTau22 model, only abnormal accumulation of ubiquitin was detected. These results demonstrate significant alterations of the proteolytic pathways in both models of proteinopathy even though they were differentially affected. Preclinical studies in transgenic models able to reproduce the pathogenic mechanisms of patients will allow the identification of novel therapeutic targets and to test effective treatments. Compounds able to reduce the burden of toxic proteins might be an alternative pharmacological approach to AD and other tauopathies.