Lysosomal Fusion Dysfunction as a Unifying Hypothesis for Alzheimer's Disease Pathology

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.

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…Finally, there is increasing evidence that vulnerable cellular protein turnover pathways (e.g. macroautophagy) are damaged and diverted by an excess of non-MT-associated tau [175,[180][181][182]. Proteomic analysis of a neuroblastoma exosomal-associated proteome consistent with this is presented in Figure 1.…”

The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease

“…Well known pathological hallmarks of AD include extracellular amyloid plaques, composed of A␤ fragments, and intracellular neurofibrillary tangles of the microtubule-binding protein Tau (66). However, these lesions appear later in disease progression, and efforts are under way to identify initial, treatable signs of dysfunction in AD.…”

“…These and many other data have been consolidated into a unifying hypothesis centering on vesicle trafficking dysfunction in AD. In this context, our demonstration that NHE6 alters APP processing implicates endosomal pH as an important modulator of amyloidogenic A␤ production and potentially of Tau aberrations (66). Notably, NHE6 deletion in mice leads to cellular phenotypes reminiscent of AD, including endosomal-lysosomal dysfunction, accumulation of unesterified cholesterol in endosomes, and neurodegeneration (69), although amyloidogenesis remains to be evaluated.…”

The role of extracellular vesicles in the progression of neurodegenerative disease and cancer

“…This could be potentially precarious for cells that are already at risk of degeneration from pre-existing genetic mutations, environmental toxins, and mutagens that alter cellular machinery and function. EVs investigated in cell culture models of neurodegeneration have been shown to carry proteins prone to aggregation, a hallmark of many neurodegenerative disorders [31]. Transfer of protein from a diseased cell to a healthy cell may lead to accumulation and aggregation of the protein in the target cell, where accumulation and aggregation of these proteins is linked to pathogenesis of neurodegenerative diseases.…”