PEAβ Triggers Cognitive Decline and Amyloid Burden in a Novel Mouse Model of Alzheimer’s Disease

Abstract

Understanding the physiopathology of Alzheimer’s disease (AD) has improved substantially based on studies of mouse models mimicking at least one aspect of the disease. Many transgenic lines have been established, leading to amyloidosis but lacking neurodegeneration. The aim of the current study was to generate a novel mouse model that develops neuritic plaques containing the aggressive pyroglutamate modified amyloid-β (pEAβ) species in the brain. The TAPS line was developed by intercrossing of the pEAβ-producing TBA2.1 mice with the plaque-developing line APPswe/PS1ΔE9. The phenotype of the new mouse line was characterized using immunostaining, and different cognitive and general behavioral tests. In comparison to the parental lines, TAPS animals developed an earlier onset of pathology and increased plaque load, including striatal pEAβ-positive neuritic plaques, and enhanced neuroinflammation. In addition to abnormalities in general behavior, locomotion, and exploratory behavior, TAPS mice displayed cognitive deficits in a variety of tests that were most pronounced in the fear conditioning paradigm and in spatial learning in comparison to the parental lines. In conclusion, the combination of a pEAβ- and a plaque-developing mouse model led to an accelerated amyloid pathology and cognitive decline in TAPS mice, qualifying this line as a novel amyloidosis model for future studies.

Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease

“…In addition, Aβ pE3-42 and Aβ 4-42 when expressed together elicited neurological deficits, which were significantly stronger as compared to expression of Aβ pE3-42 or Aβ 4-42 alone [ 43 ]. Neuronal expression of Aβ pE3-42 triggered amyloid-plaque load and memory deficits when crossed to amyloid-plaque AD mouse models [ 44 , 45 ].…”

Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease

“…The pyroglutamate-modified peptides accumulate a decade prior to the symptom onset, yet their relative abundance in the AD brain is approximately threefold higher compared to the untruncated forms, making them a superior disease-specific target [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Furthermore, they are an active component of the amyloid cascade pathogenesis rather than a harmless bystander and capable of promoting the conversion of Aβ 42 into toxic oligomers in a prion-like manner [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. The most valuable evidence in favor of targeting pE 3 Aβ is the recent clinical trial performance of donanemab, a humanized IgG1 monoclonal antibody generated from mouse mAb, mE8-IgG2a [ 31 , 32 ].…”