Mechanisms of DiseaseCytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease
Introduction
Pathogenesis of Alzheimer's disease is characterised by age-dependent cerebral deposition of β-amyloid (Aβ) peptides, which are 39–43 aminoacid residues long and are generated by endoproteolytic cleavage of the β-amyloid precursor protein (β-APP). The Aβ1–42 isoform is enriched in neocortical deposits,1 is overproduced in people with familial Alzheimer's disease,2 and contributes to disease-associated oxidative stress, protein aggregation, and neurotoxic effects.3
The human lens is also vulnerable to age-dependent degenerative changes and shows progressive deposition of insoluble protein and extensive oxidative damage.4, 5 Early-onset cataracts and Alzheimer's disease are typical comorbid disorders in adults with Down's syndrome6 and in those with familial Danish dementia,7 an Alzheimer's disease variant with cerebral Aβ amyloidosis. Evidence shows that Aβ is expressed in rodent and monkey lens.8 Conversely, αB-crystallin—an abundant cytosolic lens protein and small heat-shock protein with molecular chaperone properties9—is expressed in brain of individuals with Alzheimer's disease.10 Moreover, Aβ interacts with αB-crystallin in vitro11, 12 and in Aβ-expressing transgenic Caenorhabditis elegans.13
Despite speculation8, 14, 15 about the possibility of overlapping Alzheimer's disease-associated molecular pathological findings in the lens and brain of people with this disorder, to our knowledge, no study to date has investigated this hypothesis in man. Thus, we aimed to investigate this hypothesis.
Section snippets
Samples
The study adhered to hospital regulations, national laws, and the Declaration of Helsinki. Procurement of tissue specimens for this study was approved by institutional review boards at the Massachusetts General Hospital and the Massachusetts Eye and Ear Infirmary, Boston, MA, USA. We obtained informed consent for research use of the brain and both eyes from next-of-kin relatives. Lenses were dissected from intact globes obtained through collaborative arrangement with the Massachusetts
Results
We first identified and characterised β-APP and Aβ in the adult human lens (Figure 1, Figure 2, Figure 3). We detected full-length β-APP (110 kD and 130 kD) by affinity purification and western blot with monoclonal antibody 6E10, an antibody that detects the Aβ region of β-APP (figure 1). We also detected full-length β-APP in the B3 human lens epithelial cell line and primary human lens epithelial cells by western blot with antibodies against the C-terminal (A8717) and N-terminal (22C11)
Discussion
We have identified Aβ1–42 and Aβ1–40 in the human lens and Aβ1–40 in human primary aqueous humour. Our findings show that concentrations of Aβ1–42 and Aβ1–40 in the human lens, and Aβ1–40 in primary human aqueous humour, are comparable with those in aged human cerebral cortex and cerebrospinal fluid, respectively.24 We also noted increased deposition of electron-dense Aβ-immunoreactive aggregates within lens fibre-cell cytoplasm in the supranuclear subregion of lenses from people with
GLOSSARY
- electrospray ionisation mass spectrometry
- Analytical technique for the study of large molecules, especially proteins and peptides. The technique derives detailed information about molecular weights and structures from very small sample quantities. Electrospray ionisation refers to the methods by which the molecule under analysis is charged, or ionised. In this technique, charged droplets are generated by spraying the sample solution under a strong electric field. Ionisation occurs by protonation
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