Endocytosis and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia. The pathogenesis of AD still remains unclear, including two main hypotheses: amyloid cascade and tau hyperphosphorylation. The hallmark neuropathological changes of AD are extracellular deposits of amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Endocytosis plays an important role in a number of cellular processes including communication with the extracellular environment, nutrient uptake, and signaling by the cell surface receptors. Based on the results of genetic and biochemical studies, there is a link between neuronal endosomal function and AD pathology. Taking this into account, we can state that in the results of previous research, endolysosomal abnormality is an important cause of neuronal lesions in the brain. Endocytosis is a central pathway involved in the regulation of the degradation of amyloidogenic components. The results of the studies suggest that a correlation between alteration in the endocytosis process and associated protein expression progresses AD. In this article, we discuss the current knowledge about endosomal abnormalities in AD.

Keywords: Alzheimer’s disease; Amyloid-β; Amyloidogenic process; Endocytosis; Endosome secretion; Tau protein.

Fig. 1

Graphical presentation representing endocytosis. In endocytosis process, various extracellular components unbound or recognized by membrane-localized receptors become transported into plasma membrane–derived vesicles. These structures may serve to recycle the material back to the plasma membrane or dispatch it to lysosomes for future degradation

Fig. 2

Hypothesized model of endocytosis pathway in Alzheimer’s disease (AD). In AD, endocytosis resulted in forming increased deposition of Aβ peptides by omitting lysosomal digestion of processed endosomes. Increased activation of mTOR signaling leads to inhibition of CAV-1 expression and hyperphosphorylation of the tau protein degradation of CAV-1-rich caveolae resulting in decreased level of this marker in AD-affected brain tissue

Fig. 3

Regulation of clathrin-mediated endocytosis (CME) by PICALM. (A) In a healthy brain, PICALM interacts with adaptor protein (AP) and clathrin at the plasma membrane. PICALM participates in CME and facilitates the formation of clathrin-coated vesicles (CCVs). This provides Aβ clearance. (B) PICALM and clathrin depletion in AD brain limited or stopped Aβ clearance. This increases the distribution of Aβ, intensifying neurotoxicity to neurons. In AD, abnormally cleaved PICALM was also associated with neurofibrillary tangles, co-localizing with conformationally abnormal and hyper-phosphorylated tau (P-tau) which contributes to endocytic dysfunction in AD

Fig. 4

Graphical presentation representing the theoretical basis of Aβ accumulation in the brain tissue. Aβ deposits in the brain cause the migration of astrocytes and microglial cells into the region of plaque formation. Biological task of these cells is to phagocytose the formed lesions. Heterogeneity in proteolytic cleavages during Aβ generation and the relevant post-translational modification processes of Aβ may translate into the rate of amyloid aggregate formation, their neurotoxicity, and the effect of plaques against phagocytic cells. The symbols of the stop sign and the plus sign refer to the intensity of a given process or to the effect of increased or decreased endocytosis in relation to selected types of cells making up the nervous tissue