Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Abstract

This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iA␤), and the mechanism of an age-related increase in iA␤ in adult AD-model mouse neurons. A new end-specific antibody for A␤ 45 and another for aggregated forms of A␤ provide new insight into the composition of iA␤ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iA␤ levels containing aggregates of A␤ 45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iA␤ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iA␤ and rapidly increased following a brief metabolic stress with glutamate. A␤PP-CTF, A␤ 45 , and aggregated A␤ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iA␤ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long A␤s by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iA␤ processing may lead to application of countermeasures to prolong dementia-free health span. human clinical trials [4]. Although gamma-secretase inhibitors were screened on the basis of their inhibition of the secretion of A␤, a detailed analysis of the mechanism indicated that Semagacestat slows the tripeptide carboxypeptidase terminal triming of the primary products of gamma-secretase endoproteolysis leading to the accumulation of "long A␤s" ending at residues 45, 46, 48, and 49 of the A␤ sequence (Fig. 1), similar to many of the FAD mutations in presenilin, which interfere with the processivity of the tripeptidase trimming [5][6][7]. These results suggest that the reason that Semagacestat and Avagacestat [8] caused cognitive worsening is the same reason that FAD mutations in presenilins cause early onset

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…Mitochondria are organelles central to brain energy processes, and altering glucose availability or dysregulating oxidative phosphorylation can have direct effects on neuronal function and cognitive health (Picard and McEwen, 2014;Anderson, 2018). Recent reports have hypothesized that Aβ may initiate mitochondrial dysfunction, and one theory proposes that Aβ raises cytosolic calcium levels, inhibiting oxidative phosphorylation and, therefore, ATP production (Cardoso et al, 2001;Eckert et al, 2010;Spuch et al, 2012;Kaminsky et al, 2015;Brewer et al, 2020). Moreover, mitochondria delivery to needed brain regions is dependent on tau, a protein related to microtubules (Quintanilla et al, 2012;Amadoro et al, 2014).…”

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

“…In addition, a part of iAβ may originate from extracellular sources entering the cells by receptor mediated internalization [127]. According to a very recent hypothesis, fast aggregation of long Aβs (43 to 52 AA residues) is the main component of the iAβ assemblies [129]. Subcellularly, the endoplasmic reticulum-intermediate compartment and the endosomal-lysosomal system participate in iAβ generation [130,131].…”

“…Activated microglia also plays an important role in the formation of amyloid plaques [128]. Very recent experimental data have also revealed that aggregated iAβ co-localized mostly with mitochondria and endosomes and much less with lysosomes in a 3xTg mouse model of AD [129]. Overexpression of Aβ and iAβ formation causes different mitochondrial dysfunctions (inner transport, axonal transport of mitochondria, and depletion in the synapses) [133].…”

Plasma membrane vesicles of human umbilical cord mesenchymal stem cells ameliorate acetaminophen-induced damage in HepG2 cells: a novel stem cell therapy

“…3). When cells grow older and eventually turn into senescent, they accumulate a large amount of damaged and dysfunctional organelles, which have been implicated to play a causal role in the development of various aging diseases such as Alzheimer's disease and lysosomal storage diseases [25,26]. Organelles in PMVs of hUCMSCs are probably intact and functional.…”