Membrane pathology and microglial activation of mice expressing membrane anchored or membrane released forms of Aβ and mutated human Alzheimer's precursor protein (APP).

AimsAlzheimer'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 (PrPd) are found in prion disease but morphological changes of membranes are not associated with A in Alzheimer's disease. Membrane changes occur in all prion diseases where PrPd is attached to cell membranes by a glycosyl-phosphoinositol (GPI) anchor but are absent from transgenic mice expressing anchorless PrPd. Here we investigate whether GPI membrane attached A may also cause prion-like membrane lesions. MethodsWe used immunogold electron microscopy to determine the localization and pathology of A accumulation in groups of transgenic mice expressing anchored or unanchored forms of A or mutated human Alzheimer's precursor protein. ResultsGPI attached A did not replicate the membrane lesions of PrPd. However, as with PrPd in prion disease, A peptides derived from each transgenic mouse line initially accumulated on morphologically normal neurite membranes, elicited rapid glial recognition and neurite A was transferred to attenuated microglial and astrocytic processes. ConclusionsGPI attachment of misfolded membrane proteins is insufficient to cause prion-like membrane lesions. Prion disease and murine A amyloidosis both accumulate misfolded monomeric or oligomeric membrane proteins that are recognized 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 PrPd to endolysosomes, activated microglial cells in murine A amyloidosis are not as efficient phagocytes.