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Lysosomal fusion dysfunction as a unifying hypothesis for Alzheimer's disease pathology - PubMed

Lysosomal fusion dysfunction as a unifying hypothesis for Alzheimer's disease pathology

Kristen E Funk et al. Int J Alzheimers Dis. 2012.

Abstract

Alzheimer's disease is characterized pathologically by extracellular senile plaques, intracellular neurofibrillary tangles, and granulovacuolar degeneration. It has been debated whether these hallmark lesions are markers or mediators of disease progression, and numerous paradigms have been proposed to explain the appearance of each lesion individually. However, the unfaltering predictability of these lesions suggests a single pathological nidus central to disease onset and progression. One of the earliest pathologies observed in Alzheimer's disease is endocytic dysfunction. Here we review the recent literature of endocytic dysfunction with particular focus on disrupted lysosomal fusion and propose it as a unifying hypothesis for the three most-studied lesions of Alzheimer's disease.

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Figures

Figure 1
Figure 1

Intracellular vesicular trafficking pathways. Endocytosed surface proteins, such as APP, are delivered to the endosomal system by internalization. Internalized membrane proteins can be sorted into intralumenal vesicles of the MVB by sequential activity of ESCRTs 0, I, II, and III or delivered to the extracellular environment by the recycling endosome. Mature MVBs fuse with either the autophagosome of the autophagic pathway to form the amphisome or directly with the lysosome, which donates degradative hydrolases, creating the autolysosome where complete degradation of the sequestered material occurs. Alternatively, the multivesicular body can fuse with the plasma membrane, resulting in the exosomal secretion of the intralumenal vesicles and their internalized cargo.

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