Excess βCTF, not Aβ: The culprit in Alzheimer-related endocytic dysfunction

The article by Jiang et al. (1) in this issue of PNAS goes a good way toward explaining early consequences of elevated expression of β-amyloid precursor protein (βAPP) and its β-secretase-cleaved carboxyl-terminal fragment (βCTF) in the endocytic dysfunction present early on in Alzheimer’s disease (AD) and Down’s syndrome (DS or trisomy 21). The authors pose a straightforward question: is duplication of the βAPP gene in DS sufficient to precipitate endocytic dysfunction? Using an elegantly simple approach in fibroblasts from individuals with trisomy 21 (3N), the authors show that either suppressing the expression of the extra βAPP gene by shRNA or decreasing the production of βCTF by inhibiting the βAPP β-secretase, BACE-1, reverses the dramatic pathologic changes in endocytic morphology (endosome enlargement) and function (accelerated uptake) noted in trisomy 21 or in βAPP overexpressing 2N fibroblasts. Their finding that overexpression of a mutated form of βAPP lacking the BACE-1 cleavage site in 2N fibroblasts did not produce the endocytic dysfunction showed conclusively that the mediating factor in the βAPP-related induction of endocytic dysfunction is βCTF. However, just to be sure that the endocytic anomalies necessitated only βCTF overexpression, they also showed that similar endocytic dysfunction is elicited when β amyloid (Aβ) production is reduced and βAPP and βCTF production is increased by γ-secretase inhibition in 2N cells. Findings such as these signify an important change, perhaps a sea change, in our understanding of the potential pathogenic role of overexpressing βAPP, relative to that of Aβ, at least in the arena of early endocytic dysfunction and its downstream consequences in AD and DS. Although Aβ continues to be the principal focus of investigations into both the causes and consequences of AD, these and other findings are beginning to highlight the fundamental importance of Aβ-independent pathogenic roles of βAPP and its various proteolytic products in AD.

βAPP Rises in Alzheimer-Related Neural Injury and Neuroinflammation

The mediating factor in the βAPP-related induction of endocytic dysfunction is βCTF.

The βAPP-induced endosomal pathologies noted by Jiang et al. (1) may be related to and likely accompany other early events that occur before the development of the neuritic Aβ plaques in DS. For example, glial activation with overexpression of the proinflammatory cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B (2) accompanies the dramatic overexpression of βAPP in brains of DS fetuses (3).As further evidence of a seminal role of βAPP and its mediating products in sporadic AD, neuronal overexpression of βAPP with activation of glia and overexpression of these cytokines is an early and prominent response in conditions that increase risk for development of AD, including traumatic brain injury (TBI), excitotoxicity as in epilepsy, viral infections as in AIDS, and more subtle insults such as aging (4). In vitro simulation of stress-induced increases in neuronal βAPP are accompanied by the release of elevated levels of secreted nonamyloidogenic βAPP fragments (sAPP). This serves as a mediating factor that triggers microglial activation (5), and the consequence is the cytokine cycle, which precipitates and perpetuates the elevated expression of each of the precursor molecules necessary for production of the neuropathological entities characteristic of sporadic AD (6).

βAPP, Endosomes, and Neurodegeneration

In DS (7, 8) and in individuals with βAPP gene duplication without chromosome 21 triplication (9 –11), βAPP gene duplication is an Alzheimergenic event. In a mouse model of DS (TS65Dn), endocytic anomalies are shown to interfere with normal nerve growth-factor (NGF) trophic support (12). Both of these abnormalities and degenerative changes of basal forebrain cholinergic neurons are ameliorated by suppressing the overexpression of βAPP (13, 14). These findings and the importance of NGF in cholinergic cell maintenance are evidence of a link between the early endocytic dysfunctions in DS and AD and the cholinergic dysfunction in both diseases. Moreover, in vitro evidence of excess βAPP and sAPP driving IL-1 release and the resultant increases in both AChE synthesis and activity (15) suggests that the early and sustained high expression of IL-1, βAPP, and its cleavage fragments βCTF and sAPP in DS is related to the endocytic dysfunction, neuroinflammation, and cholinergic dysfunction in DS and sporadic AD.

Brain Aging, βAPP, and Endosome Mistrafficking

As further evidence of the importance of maintaining neuronal levels of βAPP in stressful settings, neuron somal βAPP is elevated with aging (16). Conversely, βAPP expression is decreased in somas of neurons proximal to Aβ plaques in normal aging and in AD, and such βAPP seems to be redistributed from the neuron soma to dystrophic neurites (16), swollen stretches of axons, or dendrites containing mainly stalled vesicular traffic from the endocytic and autophagic pathways (17). These findings may be related to the accelerated endocytic activity and downstream dysfunction observed early on in DS and AD described in Jiang et al. (1) in this issue of PNAS.

The revelation that excess βAPP and its mediating factor βCTF, rather than Aβ, are the culprits in endocytic dysfunction in DS, together with the findings of other investigators regarding a role for overexpression of neuronal βAPP as a result of AD risk-conferring conditions, not only pinpoints βAPP-related targets for development of therapeutic interventions to prevent or forestall pathogenesis, but as importantly, it highlights the possibility that excess βAPP and its mediating factors such as βCTF and sAPP are more involved as initiators of pathogenesis than has previously been recognized.