Amyloid-β in the Cerebrospinal Fluid of APP Transgenic Mice Does not Show Prion-like Properties

Abstract

Early diagnosis of Alzheimer`s disease (AD) is currently difficult and involves a complex approach including clinical assessment, neuroimaging, and measurement of amyloid-β (Aβ) and tau levels in cerebrospinal fluid (CSF). A better mechanistic understanding is needed to develop more accurate and even presymptomatic diagnostic tools. It has been shown that Aβ derived from amyloid-containing brain tissue has prion-like properties: it induces misfolding and aggregation of Aβ when injected into human amyloid precursor protein (APP) transgenic mice. In contrast, Aβ in the CSF has been less studied, and it is not clear whether it also exhibits prion-like characteristics, which might provide a sensitive diagnostic tool. Therefore, we collected CSF from APP transgenic mice carrying the Swedish mutation (APP23 mice), and injected it intracerebrally into young mice from the same transgenic line. We found that CSF derived Aβ did not induce increased β-amyloidosis, even after long incubation periods and additional concentration. This suggests that Aβ present in the CSF does not have the same prion-like properties as the Aβ species in the brain.

Cerebrospinal fluid from Alzheimer’s disease patients promotes tau aggregation in transgenic mice

“…The here observed tau seeding competence of AD patients’ CSF contrasts our earlier findings in seeding experiments with Aβ. There, even very long seeding times after inoculation of concentrated human or murine Aβ comprising CSF into APP transgenic host mice failed to provide evidence for the presence of bioactive Aβ seeds in the CSF compartment [16, 35]. The here described biological tau seeding activity of CSF is however not entirely surprising.…”

“…Given the physiologically low tau concentrations in CSF in the ng/ml range, the samples were concentrated as previously described (Additional file 1: Figure S1) [16, 35]. After concentration, no significant difference of the total tau levels between the two groups was measured by ELISA (156 ng/ml / 204,6 ng/ml, P = 0.65, Additional file 1: Figure S2).…”

“…In order to obtain reasonable tau levels in small volumes that could be injected into mouse brains, CSF samples were concentrated [35]. In brief, 10 ml CSF per patient, was lyophilized (− 80 °C, 0.01 mbar vacuum pressure), reconstituted in sterile H 2 O and dialyzed (using Float-A-Lyzer G2, 1kD, Spectrum Labs) to reduce the salt load, re-lyophilized, and finally reconstituted in about 10 μl H 2 O (Additional file 1: Figure S1).…”

“…Information on the prion-like properties of Aβ and tau from CSF in AD is limited. It has been shown that CSF amyloid-β does not exhibit prion-like properties in vivo [16, 35]. Recently, two studies reported a seeding-like potential of CSF-derived tau in vitro [31, 38].…”

Sequence-to-Structure Relation in Proteins-Amyloidogenic Proteins with Chameleon Sequences

“…Improper folding results in pathological proteins and leads to a variety of medical conditions jointly referred to as misfolding diseases [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Among such proteins are prionsmisfolded structures characterized by major conformational changes which produce multimeric assemblies of β-sheets, resulting in highly deleterious health effects [15][16][17][18][19][20].…”