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The APMAP interactome reveals new modulators of APP processing and beta-amyloid production that are altered in

Hermeto Gerber1,2,3, Sebastien Mosser1,2, Benjamin Boury-Jamot4

  • 1Foundation Eclosion, CH-1228, Plan-les-Ouates, Switzerland.

Acta Neuropathologica Communications
|February 2, 2019
PubMed

Insights

The adipocyte plasma membrane-associated protein (APMAP) deficiency worsens Alzheimer's disease (AD) symptoms and increases amyloid-beta (Aβ) production. APMAP interactors modulate Aβ generation, with some reduced in human AD brains.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • The adipocyte plasma membrane-associated protein (APMAP) is expressed in the brain and interacts with γ-secretase, an enzyme involved in amyloid-beta (Aβ) production.
  • Aβ peptides are implicated in the pathogenesis of Alzheimer's disease (AD).

Purpose of the Study:

  • To investigate the neurobiological functions of APMAP in memory and Aβ formation.
  • To explore the link between APMAP, AD pathology, memory impairment, and Aβ pathology.
  • To identify novel APMAP interactors and their roles in regulating amyloid precursor protein (APP) processing and Aβ production.

Main Methods:

  • Generation of a novel mouse line lacking APMAP.
  • Behavioral investigations, including spatial learning and memory tests.
  • Development of a high-grade purification procedure for APMAP protein complexes.
  • Biochemical characterization of APMAP interactomes.
  • Analysis of human brain samples from verified AD cases.

Main Results:

  • Mice lacking APMAP exhibited spatial learning and memory deficiencies.
  • Constitutive deletion of APMAP exacerbated spatial memory deficits and increased Aβ production and deposition in an AD mouse model.
  • Identification of novel APMAP interactors, including HSPA1A, CD-M6PR, clusterin, calnexin, arginase-1, PTGFRN, and CI-M6PR/IGF2R.
  • HSPA1A and CD-M6PR negatively regulated APP processing and Aβ production.
  • Clusterin, calnexin, arginase-1, PTGFRN, and CI-M6PR/IGF2R positively regulated APP and Aβ production.
  • Several identified interactors are involved in the autophagy-lysosome system, suggesting its role in modulating APP metabolism.
  • Increased alternative splicing of APMAP and decreased levels of HSPA1A and CD-M6PR were observed in human AD brains.

Conclusions:

  • APMAP plays a crucial role in regulating spatial memory and Aβ production.
  • APMAP interactors significantly influence APP processing and Aβ generation, highlighting potential therapeutic targets.
  • Dysregulation of APMAP and its interactors, particularly HSPA1A and CD-M6PR, may contribute to AD pathogenesis.
  • The autophagy-lysosome pathway is implicated in modulating APP metabolism and Aβ generation, further supported by APMAP interactor findings.
Keywords:
APMAP interactomeAPMAP-KOAlternative splicingAlzheimer’s diseaseAβ productionLearning and memoryNeurodegeneration

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