Increased Neuronal Endocytosis and Protease Delivery to Early Endosomes in Sporadic Alzheimer’s Disease: Neuropathologic Evidence for a Mechanism of Increased β-Amyloidogenesis

Abstract

The early endosome is the first vacuolar compartment along the endocytic pathway. It is the site of internalization and initial processing of amyloid precursor protein (APP) and apolipoprotein E (ApoE), two proteins of etiological importance in Alzheimer's disease, and a putative site of ␤-amyloid peptide (A␤) formation. Here, we identify early endosomes in human pyramidal neurons, using specific compartmental markers and morphometry, and show that in Alzheimer's disease individual endosomes display up to 32-fold larger volumes than the normal average. Endosomal enlargement contributed to an average 2.5-fold larger total endosomal volume per neuron, implying a marked increase in endocytic activity. Endosomal alterations were evident in most pyramidal neurons in Alzheimer brain, detectable at early stages of the disease but absent in several other neurodegenerative disorders examined. In addition, mature and proenzyme forms of the proteases cathepsin B and cathepsin D, a candidate APP secretase, were identified in most early endosomes in Alzheimer brains but were detectable in only a minor proportion of endosomes in normal brain. Expression of the cation-dependent 46 kDa mannose 6-phosphate receptor was elevated in pyramidal neurons of Alzheimer brains, which could be a possible basis for the altered cathepsin trafficking pattern. Enhanced endocytic activity, coupled with increased trafficking to endosomes of proteases, which may have the ability under pathological conditions to generate A␤, constitutes a potential mechanism by which ␤-amyloidogenesis may become accelerated in sporadic AD and also be subject to influences by ApoE.

Endosomal Nox2 Facilitates Redox-Dependent Induction of NF-κB by TNF-α

“…Another variable to consider is changes in redoxosome size; our estimates for the flux of O 2 -are based on a diameter of 200 nm (Table 1). This estimate is consistent with the literature for early endosomes (7,8,28,43) and with our own studies evaluating redoxosomes by EM (42). However, endosome size is very dynamic and changes rapidly as endosomes traffic and fuse with other compartments.…”

Differential Regulation of Amyloid-β Endocytic Trafficking and Lysosomal Degradation by Apolipoprotein E Isoforms

“…A␤ aggregates also destabilize the lysosomal membrane (39), which further compromises lysosomal function and induces leakage of hydrolases into cytoplasmic compartment, contributing to ultimate neuronal death (40,41). Several studies have shown that endosome/lysosome abnormality, including their enlargement, is often induced in early stages of AD (18,19,42,43). Furthermore, presenilin 1 (PSEN1) mutations, causing early-onset AD, induce a disturbed lysosomal/autophagy phenotype by affecting lysosome acidification and proteolysis (44).…”

Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity

“…These mechanisms include modulation of the deposition and clearance of amyloid ␤ (A␤) peptides and the formation of plaques (9 -15), modulation of A␤-caused synaptic and cholinergic deficits (16), acceleration of age-and excitotoxicity-related neurodegeneration (17), impairment of the antioxidative defense system and mitochondrial function (18 -21), dysregulation of neuronal signaling pathways (22), altered phosphorylation of tau and neurofibrillary tangle formation (23)(24)(25)(26)(27)(28), depletion of cytosolic androgen receptor levels in the brain (29,30), potentiation of A␤-induced lysosomal leakage and apoptosis in neuronal cells (31), and promotion of endosomal abnormalities linked to A␤ overproduction (32)(33)(34). The mechanisms of these apoE4-mediated detrimental effects are largely unknown.…”