Real-time heterogeneity of supramolecular assembly of amyloid precursor protein is modulated by an endocytic risk factor PICALM
Cell. Mol. Life Sci.. 2023-09-20; 80(10):
DOI: 10.1007/s00018-023-04939-w
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Belapurkar V(1)(2), Mahadeva Swamy HS(#)(1)(3), Singh N(#)(1), Kedia S(1)(4), Setty SRG(5), Jose M(1), Nair D(6).
Author information:
(1)Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012, India.
(2)Interdisciplinary Institute for Neuroscience CNRS UMR5297, University of Bordeaux, Bordeaux, France.
(3)Tata Institute for Genetics and Society, Bengaluru, India.
(4)Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
(5)Department of Microbiology and Cell Biology, Indian Institute of Science,
Bangalore, 560012, India.
(6)Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012,
India. .
(#)Contributed equally
Recently, the localization of amyloid precursor protein (APP) into reversible
nanoscale supramolecular assembly or “nanodomains” has been highlighted as
crucial towards understanding the onset of the molecular pathology of
Alzheimer’s disease (AD). Surface expression of APP is regulated by proteins
interacting with it, controlling its retention and lateral trafficking on the
synaptic membrane. Here, we evaluated the involvement of a key risk factor for
AD, PICALM, as a critical regulator of nanoscale dynamics of APP. Although it
was enriched in the postsynaptic density, PICALM was also localized to the
presynaptic active zone and the endocytic zone. PICALM colocalized with APP and
formed nanodomains with distinct morphological properties in different
subsynaptic regions. Next, we evaluated if this localization to subsynaptic
compartments was regulated by the C-terminal sequences of APP, namely, the
“Y682ENPTY687” domain. Towards this, we found that deletion of C-terminal
regions of APP with partial or complete deletion of Y682ENPTY687, namely, APP-Δ9
and APP-Δ14, affected the lateral diffusion and nanoscale segregation of APP.
Lateral diffusion of APP mutant APP-Δ14 sequence mimicked that of a detrimental
Swedish mutant of APP, namely, APP-SWE, while APP-Δ9 diffused similar to
wild-type APP. Interestingly, elevated expression of PICALM differentially
altered the lateral diffusion of the APP C-terminal deletion mutants. These
observations confirm that the C-terminal sequence of APP regulates its lateral
diffusion and the formation of reversible nanoscale domains. Thus, when combined
with autosomal dominant mutations, it generates distinct molecular patterns
leading to onset of Alzheimer’s disease (AD).
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.