APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38

Topic: Brain proteins, microglia and lab models

Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in the brains of patients with Aβ deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aβ38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.

Key findings

• Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome.
• Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.

Why it matters

In brain tissue, the amyloid peptide Aβ38 accumulated in patients carrying APP mutations in the Aβ coding region, but was not detected in patients with APP mutations outside the Aβ domain, in patients with presenilin mutations, or in people with Down syndrome. The authors suggest these mutations favour Aβ38 accumulation and that the mechanisms of amyloid deposition in these patients may differ, but the study does not test any treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1007/s00401-012-1061-x
• PubMed: 23143229
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{moro2012-23143229,
  author  = {Moro, M. L. and Giaccone, G. and Lombardi, R. and Indaco, A. and Uggetti, A. and Morbin, M. and Saccucci, S. and Di Fede, G. and others},
  title   = {{APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38}},
  journal = {Acta neuropathologica},
  year    = {2012},
  doi     = {10.1007/s00401-012-1061-x},
  pmid    = {23143229},
  url     = {https://doi.org/10.1007/s00401-012-1061-x}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment Annals of Neurology · 1991-10-01 · usefulness score 62/100 · Brain tissue and pathology
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• Alzheimer's Disease: Genes, Proteins, and Therapy Physiological Reviews · 2001-04-01 · usefulness score 58/100 · Disease mechanisms
• APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy Nature genetics · 2005-12-20 · usefulness score 58/100 · Brain tissue and pathology
• The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia Brain : a journal of neurology · 2010-04-19 · usefulness score 57/100 · Caregiving
• Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia Archives of general psychiatry · 2012-01-01 · usefulness score 56/100 · Tau biomarkers
• The mechanism of γ-Secretase dysfunction in familial Alzheimer disease The EMBO journal · 2012-04-13 · usefulness score 55/100 · Risk genes beyond APOE
• Combined CSF tau, p-tau181 and amyloid-beta 38/40/42 for diagnosing Alzheimer's disease Journal of neural transmission (Vienna, Austria : 1996) · 2009-01-14 · usefulness score 48/100 · Tau biomarkers
• Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40 Human mutation · 2006-07-01 · usefulness score 47/100 · Risk genes beyond APOE
• Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease Archives of neurology · 2008-04-01 · usefulness score 46/100 · Risk genes beyond APOE
• Current status on Alzheimer disease molecular genetics: from past, to present, to future Human molecular genetics · 2010-04-13 · usefulness score 46/100 · Genetics

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• Clearance systems in the brain-implications for Alzheimer disease Nature reviews. Neurology · 2015-07-21 · usefulness score 56/100 · Brain tissue and pathology
• Molecular Basis of Familial and Sporadic Alzheimer's Disease Current Alzheimer research · 2016-01-01 · usefulness score 43/100 · TREM2 and immune genetics

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