Amyloid‐β protofibril levels correlate with spatial learning in Arctic Alzheimer’s disease transgenic mice

Abstract

Oligomeric assemblies of amyloid‐β (Aβ) are suggested to be central in the pathogenesis of Alzheimer’s disease because levels of soluble Aβ correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, such Aβ species have been shown to be neurotoxic, to interfere with learned behavior and to inhibit the maintenance of hippocampal long‐term potentiation. The tg‐ArcSwe model (i.e. transgenic mice with the Arctic and Swedish Alzheimer mutations) expresses elevated levels of Aβ protofibrils in the brain, making tg‐ArcSwe a highly suitable model for investigating the pathogenic role of these Aβ assemblies. In the present study, we estimated Aβ protofibril levels in the brain and cerebrospinal fluid of tg‐ArcSwe mice, and also assessed their role with respect to cognitive functions. Protofibril levels, specifically measured with a sandwich ELISA, were found to be elevated in young tg‐ArcSwe mice compared to several transgenic models lacking the Arctic mutation. In aged tg‐ArcSwe mice with considerable plaque deposition, Aβ protofibrils were approximately 50% higher than in younger mice, whereas levels of total Aβ were exponentially increased. Young tg‐ArcSwe mice showed deficits in spatial learning, and individual performances in the Morris water maze were correlated inversely with levels of Aβ protofibrils, but not with total Aβ levels. We conclude that Aβ protofibrils accumulate in an age‐dependent manner in tg‐ArcSwe mice, although to a far lesser extent than total Aβ. Our findings suggest that increased levels of Aβ protofibrils could result in spatial learning impairment.

Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?

“…Analysis for spatial learning and memory, however, revealed that 12-month-old mice with readily detectable ADDLs displayed a significant delay in acquisition when compared with non-transgenic littermates [31]. Aβ protofibril levels correlate with spatial learning in AD transgenic mice expressing human APP with the Arctic mutation [32], facilitating early intraneuronal Aβ aggregation [33]. Despite the difficulty in comparing the different studies on oligomeric Aβ species there seems to be converging evidence that they (i) are primarily formed within neurons, (ii) oligomeric Aβ species are more neurotoxic than monomeric or fibrillar Aβ in vitro, (iii) oligomeric Aβ species decrease synaptic activity.…”

Identification of Low Molecular Weight Pyroglutamate Aβ Oligomers in Alzheimer Disease

“…Hippocampal synaptic plasticity and memory were impaired at 8 months of age (46). A␤ protofibril levels correlate with spatial learning in AD transgenic mice expressing human APP with the arctic mutation (47) facilitating early intraneuronal A␤ aggregation (48). Despite the difficulty to compare the different studies on oligomeric A␤ species there seems to be converging evidence that they: 1) are primarily formed within neurons, 2) oligomeric A␤ species are more neurotoxic than monomeric or fibrillar A␤ in vitro, and 3) oligomeric A␤ species decrease synaptic activity.…”

Role of Apolipoprotein E in β-Amyloidogenesis

“…A␤ protofibrils have been identified as a toxic, soluble, and fibril-like intermediate in an in vitro A␤ fibrillization assay (22,23). It has been reported that A␤ protofibrils were detected in the brain and cerebrospinal fluid of APP transgenic mice using an antibody specific for A␤ protofibrils (42) and that passive immunization with the A␤ protofibril-specific antibody significantly reduced the amyloid burden in the brains of APP transgenic mice (43). In addition, it has been reported that E22G (Arctic) FAD mutation that alters an amino acid residue within A␤ region accelerates protofibril formation in vitro (20), as well as amyloid deposition in the brains of APP transgenic mice (44).…”