Cell-type-specific enhancement of amyloid-beta deposition in a novel presenilin-1 mutation (P117L)

Topic: Brain proteins, microglia and lab models

The presenilin-1 (PS1) gene mutation (Pro117Leu), recently identified in a Polish family is characterized by the earliest reported onset (from 24-31 years) of Alzheimer disease (AD) and a very short duration of disease (4-6 years). The neuropathology of 2 subjects with this PS1 mutation (ages at death: 35 and 37 years) was compared to four Down syndrome (DS) patients (mean age at death: 62 years) and 4 sporadic AD patients (mean age at death: 79 years with a mean duration of disease of 18 years). The Polish familial AD (FAD) patients showed a marked increase in the amyloid burden of 2 6-fold in most areas of the brain. The entorhinal cortex was an exception where the amyloid burden was similar in each category of patient. Some brain regions of the Polish FAD patients showed a massive increase of amyloid, such as the molecular layer of the cerebellum where a 7- and 25-fold increase was noted, compared with DS and sporadic AD patients respectively. The cerebellar vessel amyloid burden was also greatly increased in the FAD patients, reflecting a vascular compartment specific increase of amyloid beta deposition. The presence of this PS1 mutation has an even greater effect on both vascular and parenchymal amyloid deposition, than the overexpression of the amyloid beta precursor protein present in DS patients, suggesting that PS mutations can be a critical factor determining amyloid deposition.

@article{wegiel1998-9737546,
  author  = {Wegiel, J. and Wisniewski, H. M. and Kuchna, I. and Tarnawski, M. and Badmajew, E. and Popovitch, E. and Kulczycki, J. and Dowjat, W. K. and others},
  title   = {{Cell-type-specific enhancement of amyloid-beta deposition in a novel presenilin-1 mutation (P117L)}},
  journal = {Journal of neuropathology and experimental neurology},
  year    = {1998},
  doi     = {10.1097/00005072-199809000-00004},
  pmid    = {9737546},
  url     = {https://doi.org/10.1097/00005072-199809000-00004}
}

Key findings

• The neuropathology of 2 subjects with this PS1 mutation (ages at death: 35 and 37 years) was compared to four Down syndrome (DS) patients (mean age at death: 62 years) and 4 sporadic AD patients (mean age at death: 79 years with a mean duration of disease of 18 years).
• Some brain regions of the Polish FAD patients showed a massive increase of amyloid, such as the molecular layer of the cerebellum where a 7- and 25-fold increase was noted, compared with DS and sporadic AD patients respectively.
• The presence of this PS1 mutation has an even greater effect on both vascular and parenchymal amyloid deposition, than the overexpression of the amyloid beta precursor protein present in DS patients, suggesting that PS mutations can be a critical factor determining amyloid deposition.

Why it matters

This study describes a presenilin-1 mutation associated with very early onset Alzheimer's disease and compares amyloid deposition in those patients to Down syndrome and sporadic Alzheimer's patients. It characterizes the effect of this mutation on amyloid buildup but does not test any treatment or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1097/00005072-199809000-00004
• PubMed: 9737546
• Original source →

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