Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport

Abstract

The two pathological hallmarks of Alzheimer's disease, amyloid plaques and neurofibrillary tangles, involve two apparently unrelated proteins, the amyloid precursor protein (APP) and Tau. Although it is known that aberrant processing of APP is associated with Alzheimer's disease, the definitive role of APP in neurons is not yet clear. Tau regulates microtubule stabilization and assembly in axons and is, thus, an essential component of the microtubule-associated organelle transport machinery. Although several groups have reported physical interaction between APP and Tau, and induction of Tau phosphorylation by APP and beta-amyloid peptide, the functional connection between APP and Tau is unclear. To explore the possibility that the functions of these two proteins may somehow converge on the same cellular process, we overexpressed APPL, the Drosophila homologue of APP, along with Tau in Drosophila neurons. Panneural coexpression of APPL and Tau resulted in adults that, upon eclosion, failed to expand wings and harden the cuticle, which is suggestive of neuroendocrine dysfunction. We analyzed axonal transport when Tau and APPL were coexpressed and found that transport of axonal cargo was disrupted, as evidenced by increased retention of synaptic proteins in axons and scarcity of neuropeptide-containing vesicles in the distal processes of peptidergic neurons. In an independent approach, we demonstrated genetic interaction and phenotypic similarity between APPL overexpression and mutations in the Kinesin heavy chain (Khc) gene, the product of which is a motor for anterograde vesicle trafficking.

Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

“…The effect of APP on ⌬Tau-induced cell death is not known, though recent reports show a physical interaction between Tau and APP, as well as their coupled axonal transport (Islam and Levy, 1997;Torroja et al, 1999). Levels of both APP and Tau mRNA are elevated in Down's syndrome (Oyama et al, 1993).…”

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

“…Disrupted transport has been shown in AD (Cash et al, 2003;Praprotnik et al, 1996;Richard et al, 1989;Terry, 1996) and also amyotrophic lateral sclerosis (Williamson and Cleveland, 1999), however relatively few studies have examined this aspect of the disease (Kasa et al, 2000). Nonetheless, numerous factors implicated in AD including oxidative stress (de la Monte et al, 2000;Perry and Smith, 1997;Smith et al, 1995), APO e (Tesseur et al, 2000), and APP-L (Torroja et al, 1999) have all been shown to affect axonal transport. The observation that AbPP can serve as a kinesin cargo receptor (Kamal et al, 2000(Kamal et al, , 2001 as well as the inhibition of kinesin-dependent transport by tau overexpression (Ebneth et al, 1998;Stamer et al, 2002) should not be overlooked.…”

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

“…20 However, loss-and gain-of-function studies have revealed a role for APPL in synapse differentiation and axonal transport. [22][23][24] The mutant loechrig presents with a neurodegenerative phenotype that is strongly enhanced by Appl d mutants. 25 Overexpression of wild-type and mutant APPL proteins has also been shown to cause abnormal neurite outgrowth.…”