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Review
. 2024 Oct 2;481(19):1297-1325.
doi: 10.1042/BCJ20240056.

Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations

Jingqi Wang  1 , Lou Fourriere  1 , Paul A Gleeson  1
Affiliations
Review

Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations

Jingqi Wang et al. Biochem J. .

Abstract

The production of neurotoxic amyloid-β peptides (Aβ) is central to the initiation and progression of Alzheimer's disease (AD) and involves sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. APP and the secretases are transmembrane proteins and their co-localisation in the same membrane-bound sub-compartment is necessary for APP cleavage. The intracellular trafficking of APP and the β-secretase, BACE1, is critical in regulating APP processing and Aβ production and has been studied in several cellular systems. Here, we summarise the intracellular distribution and transport of APP and its secretases, and the intracellular location for APP cleavage in non-polarised cells and neuronal models. In addition, we review recent advances on the potential impact of familial AD mutations on APP trafficking and processing. This is critical information in understanding the molecular mechanisms of AD progression and in supporting the development of novel strategies for clinical treatment.

Keywords: Alzheimers disease; Golgi apparatus; amyloid precursor protein; endosomal sorting; neurons; trafficking.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. APP processing.
Full-length APP can be cleaved sequentially by different secretases to give rise to different products. (A) In the non-amyloidogenic pathway, APP is cleaved by α-secretase, producing sAPPα and C83 (CTFα) fragments. C83 (CTFα) can be further cleaved by γ-secretase, generating p3 and AICD fragments. p3 is not neurotoxic. (B) In the amyloidogenic pathway, APP is cleaved by β-secretase, producing sAPPβ and C99 (CTFβ). Subsequent cleavage of C99 (CTFβ) by γ-secretase leads to the formation of AICD and Aβ. Soluble Aβ can be secreted and aggregate into amyloid plaques, a hallmark of Alzheimer's disease. (C) The protein sequence of APP695 close to the secretase cleavage sites. Sequence of the transmembrane domain (TMD, in bold), and flanking sequences of the cytoplasmic tail and the luminal domain of APP are shown. The cleavage sites of α-, β- and γ-secretases are illustrated in blue, red and black, respectively.
Figure 2.
Figure 2.. Trafficking itineraries of APP and the β-secretase BACE1 in non-polarised cells.
Intracellular trafficking itineraries of APP and the β-secretase BACE1 in non-polarised cells are illustrated in blue and red, respectively. Both APP and BACE1 are synthesised in the endoplasmic reticulum (ER) and transported to the Golgi apparatus. APP and BACE1 segregate within the Golgi stack and are sorted into different transport carriers at the trans-Golgi network (TGN). The bulk of APP is transported to the early endosomes and then transported along the late endosome-lysosome pathway in cultured cells using protocols to synchronise trafficking of APP from the ER [47,48]. Low levels of APP are transported to the cell surface as quantified by TIRF [48] and are present at steady state as assessed by subcellular fractionation [49]. In contrast, BACE1 is sorted directly to the plasma membrane [50]. BACE1 can be actively internalised and recycled through the recycling endosomes, while APP showed minimal localisation to the recycling endosomes. Hence, the TGN and the early endosomes serve as potential sites for the β-cleavage of APP.
Figure 3.
Figure 3.. APP trafficking and sites of processing in primary rodent neurons.
APP trafficking in primary rodent neuronal models is complex, as neurons are comprised of polarised subdomains (axon and dendrites) in addition to the cell body (soma). APP is distributed in primary rodent neurons in the soma, dendrite, and axon, as well as both pre- and post-synapses. In the soma, APP is mainly associated with the Golgi and Golgi-derived vesicles, and the early and recycling endosomes. Newly synthesised APP can be transported to the axon and dendrites. APP can also be transcytosed from the axonal domain to the dendrites. Limited levels of APP and BACE1 co-localisation have been observed in the Golgi and Golgi-derived vesicles, as well as recycling endosomes.
Figure 4.
Figure 4.. Mapping of mutations in APP.
The protein sequence of the transmembrane domain (TMD, bold), and the flanking sequences of the cytoplasmic tail the luminal domain of APP695 are shown. The secretases cleavage sites are illustrated as in Figure 1. The Swedish mutation, a double mutation substituting K595 and M596 to N595 and L596, is mapped adjacent to the β-cleavage site. The protective Icelandic mutation, A598T, is illustrated in green. Other pathogenic APP mutations identified in familial Alzheimer's disease are labelled in red. Details of the pathogenic mutations which map in the transmembrane domain of APP are identified in the figure table.
Figure 5.
Figure 5.. Model of the trafficking and processing of APP under healthy and disease conditions.
Under physiological conditions, APP and BACE1 are well segregated in neurons. The partitioning of APP and BACE1 regulates APP processing and is associated with only low levels of Aβ production. Under conditions which promote Alzheimer's disease, dysregulation of APP trafficking and/or processing leads to elevated levels of APP and BACE1 convergence, resulting in an increased production of intracellular Aβ probably in the Golgi apparatus (somatic and dendritic), the early endosomes and in the recycling endosomes. The production of intracellular Aβ subsequently results in organelle abnormalities, including but not limited to Golgi disruption, endosome enlargement and lysosomal abnormalities. Perturbation of the architecture and membrane subdomains of the Golgi and endosomes may then lead to dysregulated protein sorting and trafficking, a reduction in the partitioning of APP and BACE1 in membranes and a further increase APP processing and production of Aβ. The intracellular stress caused by organelle abnormalities and Aβ production could have broader effects on the intracellular organisation and trafficking (i.e.: of synaptic receptors) which then lead to neuronal defects.
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