Alzheimer’s peptide: A possible link between glaucoma, exfoliation syndrome and Alzheimer’s disease

Dear Sir, The association between glaucoma and exfoliation syndrome (XFS) is convincingly established. Amorphous masses are formed in the optic nerve in glaucomatous atrophy (Aasved 1971) and the exfoliation material consists of cross-banded fibrils and filamentous subunits in amorphous ground substance (Damji et al. 1998), and both diseases occur with increasing frequency with age. Vascular involvement is seen as disc haemorrhages in glaucoma and as newly formed iris capillaries in XFS (Vannas 1969), therefore vascular endothelial engagement might be a primary cause of glaucoma and XFS. The idea that these diseases might be pathogenetically similar to another age related condition, namely, Alzheimer's disease (AD), was found worth testing. Alzheimer's peptide (Aβ), is a 39–43 residue fragment produced from cleavage of a large amyloid precursor protein and belongs to a family of amyloidogenic peptides whose self-initiating polymerization has been proposed as one of the pathogenic mechanisms involved in amyloid diseases such as Alzheimer's disease (AD). There is evidence consistent with this hypothesis that inflammatory mechanisms causing the accumulation of amyloid-like masses and neuronal degeneration are associated with AD and possibly with XSF (Vickers 1997). Earlier studies have shown that aqueous humour from cataractous eyes with and without XFS contains high concentrations of proteins with diverse molecular size (Ringvold et al. 1989), but the chemical composition and identities of these proteins are still largely unknown. In order to establish a possible link between the proteins involved in deposit formation in AD and XFS, we determined in aqueous humour from cataractous eyes the presence of AD-related proteins such as Aβ peptide and serine proteinase inhibitor, alpha-1-antichymotrypsin. Alpha-1-antichymotrypsin is always present in amyloid deposits in AD brain and is known to act as an inflammatory reactant and a regulator of amyloid formation (Abraham 1992; Fraser et al. 1993; Janciauskiene & Wright 1998). We also tested for another serine proteinase inhibitor, alpha-1-antitrypsin which has not been implicated in AD amyloid deposits, but is detected in the human cornea and is suggested to be an important factor controlling proteinase activity in the local inflammatory microenvironment (Boskovic & Twining 1998). Fresh aqueous humour for analysis can be obtained during cataract surgery, hardly otherwise. The subjects are aged people, sometimes with glaucoma and glaucoma therapy. For this study aqueous humour samples from 90 non-selected patients, average age 75, were collected during cataract surgery. Among the samples macular degeneration was noted in 14, diabetes in 7, iritis in 2, open angle glaucoma in 10, and XF masses in 16 cases (4 of them had both glaucoma and XF). Aqueous samples obtained from the patients diagnosed only for cataract without glaucoma and XF were used as a control group (n=68). The glaucoma cases were treated with pressure reducing-drugs such as Timolol, Pilocarpine and Xalatan. Protein profiles in samples were analysed with electrophoresis followed by immunoblotting. Representative protein profiles in the analysed samples showed high and low molecular size proteins ranging between 202 to 60 kDa and 16 to 6 kDa, respectively. It is noteworthy that the levels of lower molecular size proteins were higher in XF aqueous samples. Moreover, we found at least one of the three tested proteins, Aβ, alpha-1-antichymotrypsin and alpha-1-antitrypsin, in 41 of the 90 analysed samples. Aβ peptide was found in 38% of all cases with XFS and in 40% of all cases with glaucoma. In all of these cases, except one with XFS and two with glaucoma, alpha-1-antichymotrypsin or alpha-1-antitrypsin or both were detected. Aβ was also found in 18% of the control (non-XF) samples. We found that 80% and 69% of cases having at least one of the analysed proteins are in the groups with glaucoma or XF masses and only 40% and 41% of cases without glaucoma and XF, respectively. For the Aβ peptide the relations were similar: we found this peptide in 40% and 38% of cases with glaucoma and XF masses and 19% and 18% in those without glaucoma and XF, respectively. In addition, the Aβ was found in 4 of 14 cases with macular degeneration. A number of cases without XFS and glaucoma had no measurable levels of the Aβ peptide, but had alpha-1-antitrypsin and alpha-1-antichymotrypsin, which leads us to suggest that these proteins might reflect inflammatory processes in the eyes or clinical signs of impairment of the blood-aqueous barrier. The finding of the Aβ among cases without XF masses is not surprising when we consider the difficulties in detecting this material at a routine clinical examination (especially without pupil dilatation). Similarly, early cases of glaucoma are not diagnosed before the typical symptoms (visual field defects, high IOP) appear later in the course of the disease. In contrast, there are cases of glaucoma and XFS where no Aβ could be detected in the aqueous. A possible explanation might be that amyloid deposits once formed may deplete free soluble peptide below the levels detectable by our methods. Moreover, the possible effect of the cataract and anti-glaucomatous therapy requires consideration. Thus, even if the picture is not clear, the mere presence of AD-specific proteins in the aqueous, especially in cases with glaucoma and with XFS, raises interesting speculations around a common basic process in these age related diseases and stimulates further studies. Correspondence: Prof. T. Krakau, M.D. Ph.D. Department of OphthalmologyUniversity Hospital MalmöS-20502 Malmö, SwedenTelephone: 46 40 33 31 34e-mail: torsten.krakau@oftal.mas.lu.seSabina Janciauskiene, Ph.DDepartment of MedicinWallenberg Laboratory, Ing. 46MAS, S-20502, Malmö, SwedenFax: +46 40 33 40 71e-mail: sabina.janciauskiene@medforsk.mas.lu.se Received on December 1st, 2000.