Projects per year
AIMS: Alzheimer's disease and the transmissible spongiform encephalopathies or prion diseases accumulate misfolded and aggregated forms of neuronal cell membrane proteins. Distinctive membrane lesions caused by the accumulation of disease-associated prion protein (PrP(d) ) are found in prion disease but morphological changes of membranes are not associated with Aβ in Alzheimer's disease. Membrane changes occur in all prion diseases where PrP(d) is attached to cell membranes by a glycosyl-phosphoinositol (GPI) anchor but are absent from transgenic mice expressing anchorless PrP(d) . Here we investigate whether GPI membrane attached Aβ may also cause prion-like membrane lesions.
METHODS: We used immunogold electron microscopy to determine the localization and pathology of Aβ accumulation in groups of transgenic mice expressing anchored or unanchored forms of Aβ or mutated human Alzheimer's precursor protein.
RESULTS: GPI attached Aβ did not replicate the membrane lesions of PrP(d) . However, as with PrP(d) in prion disease, Aβ peptides derived from each transgenic mouse line initially accumulated on morphologically normal neurite membranes, elicited rapid glial recognition and neurite Aβ was transferred to attenuated microglial and astrocytic processes.
CONCLUSIONS: GPI attachment of misfolded membrane proteins is insufficient to cause prion-like membrane lesions. Prion disease and murine Aβ amyloidosis both accumulate misfolded monomeric or oligomeric membrane proteins that are recognised by glial processes and acquire such misfolded proteins prior to their accumulation in the extracellular space. In contrast to prion disease where glial cells efficiently endocytose PrP(d) to endo-lysosomes, activated microglial cells in murine Aβ amyloidosis are not as efficient phagocytes.
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- 3 Finished
1/08/10 → 31/08/15
1/05/08 → 28/02/11