Amyloid precursor protein-mediated mitochondrial regulation and Alzheimer's disease

Abstract

Despite clear evidence of a neuroprotective physiological role of amyloid precursor protein (APP) and its non-amyloidogenic processing products, APP has been investigated mainly in animal and cellular models of amyloid pathology in the context of Alzheimer's disease. The rare familial mutations in APP and presenilin-1/2, which sometimes drive increased amyloid β (Aβ) production, may have unduly influenced Alzheimer's disease research. APP and its cleavage products play important roles in cellular and mitochondrial metabolism, but many studies focus solely on Aβ. Mitochondrial bioenergetic metabolism is essential for neuronal function, maintenance and survival, and multiple reports indicate mitochondrial abnormalities in patients with Alzheimer's disease. In this review, we focus on mitochondrial abnormalities reported in sporadic Alzheimer's disease patients and the role of full-length APP and its non-amyloidogenic fragments, particularly soluble APPα, on mitochondrial bioenergetic metabolism. We do not review the plethora of animal and in vitro studies using mutant APP/presenilin constructs or experiments using exogenous Aβ. In doing so, we aim to invigorate research and discussion around non-amyloidogenic APP processing products and the mechanisms linking mitochondria and complex neurodegenerative disorders such as sporadic Alzheimer's disease. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Figure 1

APP processing and cleavage products. Non‐amyloidogenic processing of APP (right) involves cleavage by α‐secretase, resulting in the generation of sAPPα into the extracellular space and intracellular CTFα/CTF83. CTFα undergoes further cleavage by the γ‐secretase complex, yielding p3 and AICD fragments, which are further processed by caspases, producing Jcasp and C31. The amyloidogenic pathway (left) involves cleavage by β‐secretase, with a subsequent release of sAPPβ into the extracellular medium, and CTFβ/CTF99 in the membrane. Cleavage of CTFβ by the γ‐secretase complex generates Aβ peptides, AICD fragments, Jcasp and C31. Cleavage by α‐secretase occurs at a position within the sequence of Aβ, and therefore precludes its formation.

Figure 2

Mechanisms of APP regulation of mitochondrial OXPHOS metabolism. APP accumulates in the protein import channels of mitochondria (TIM/TOM), preventing the import of nuclear‐encoded mitochondrial proteins, including subunits of OXPHOS complexes (I‐IV, ATP synthase) (1). Binding of sAPPα to an unknown cell membrane receptor, potentially the InsR, may activate the PI3K/Akt pathway to decrease mtDNA transcription of OXPHOS subunits (2). APP and APP‐derived peptides can be produced and processed at MAMs (3). An accumulation of unprocessed CTF99 and AICDs in mitochondria has been linked to altered lipid composition and disruption of mitochondrial membranes that interfere with OXPHOS function (4). Pathological binding of ABAD to Aβ in mitochondria causes leakage of ROS and mitochondrial dysfunction (5), but the effects of this binding on mtDNA processing have not been investigated yet. TIM, translocase of the inner membrane; TOM, translocase of the mitochondrial outer membrane.