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Cell-type-specific enhancement of amyloid-beta deposition in a novel presenilin-1 mutation (P117L)
J Wegiel1, H M Wisniewski, I Kuchna
1New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314, USA.
Insights
A rare presenilin-1 (PS1) gene mutation causes early-onset Alzheimer disease (AD) with severe amyloid buildup in the brain and blood vessels. This PS1 mutation significantly accelerates amyloid deposition more than Down syndrome.
Area of Science:
- Neuropathology
- Genetics
- Neurodegenerative Diseases
Background:
- Familial Alzheimer disease (FAD) is linked to genetic mutations.
- Presenilin-1 (PS1) gene mutations are a known cause of FAD.
- A specific PS1 Pro117Leu mutation presents with unusually early onset and rapid progression of Alzheimer disease.
Purpose of the Study:
- To compare the neuropathology of early-onset FAD caused by the PS1 Pro117Leu mutation with Down syndrome (DS) and sporadic AD.
- To investigate the extent and distribution of amyloid burden in the brain and vasculature.
Main Methods:
- Neuropathological examination of two subjects with the PS1 mutation.
- Comparison with neuropathological data from four DS patients and four sporadic AD patients.
- Quantification of amyloid burden in various brain regions and cerebellar vasculature.
Main Results:
- The PS1 mutation subjects exhibited the earliest onset (24-31 years) and shortest disease duration (4-6 years) of AD.
- A significant increase (2-6 fold) in amyloid burden was observed in most brain areas of PS1 mutation patients.
- Massive amyloid deposition, particularly in the cerebellum (7-25 fold increase) and cerebellar vasculature, was noted in PS1 mutation patients, exceeding that in DS and sporadic AD.
Conclusions:
- The PS1 Pro117Leu mutation leads to severe amyloid deposition in both brain parenchyma and vasculature.
- This PS1 mutation has a more profound effect on amyloid deposition than the amyloid precursor protein overexpression seen in DS.
- PS1 mutations are critical determinants of amyloid deposition in Alzheimer disease.
Abstract:
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.
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