Familial British and
familial Danish dementia (FDD) are progressive
neurodegenerative disorders characterized by cerebral deposition of the amyloidogenic
peptides ABri and ADan, respectively. These
amyloid peptides start with an N-terminal
glutamate residue, which can be posttranslationally converted into a
pyroglutamate (pGlu) modified form, a mechanism which has been extensively described to be relevant for
amyloid-beta (Aβ)
peptides in
Alzheimer's disease. Like pGlu-Aβ
peptides, pGlu-ABri
peptides have an increased aggregation propensity and show higher toxicity on human
neuroblastoma cells as their nonmodified counterparts. We have generated novel N-terminal specific
antibodies detecting the pGlu-modified forms of ABri and ADan
peptides. With these
antibodies we were able to identify abundant extracellular
amyloid plaques, vascular, and parenchymal deposits in human familial British
dementia and FDD brain tissue, and in a mouse model for FDD. Double-stainings using C-terminal specific
antibodies in human samples revealed that highly aggregated pGlu-ABri and pGlu-ADan
peptides are mainly present in plaque cores and central vascular deposits, leading to the assumption that these
peptides have seeding properties. Furthermore, in an FDD-mouse model ADan
peptides were detected in presynaptic terminals of the hippocampus where they might contribute to impaired synaptic transmission. These similarities of ABri and ADan to Aβ in
Alzheimer's disease suggest that the posttranslational pGlu-modification of
amyloid peptides might represent a general pathological mechanism leading to increased aggregation and toxicity in these forms of degenerative
dementias.