The role of N-truncated Aβ peptides in Alzheimer’s Disease

by Jose Socrates Lopez Noguerola
Doctoral thesis
Date of Examination:2018-06-26
Date of issue:2018-06-29
Advisor:Prof. Dr. Thomas A. Bayer
Referee:Prof. Dr. Thomas A. Bayer
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Silvio Rizzoli
Referee:Prof. Dr. Thomas Dresbach
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Prof. Dr. Hubertus Jarry
Persistent Address: http://dx.doi.org/10.53846/goediss-6949

 

 

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Abstract

English

The N-terminally truncated pyroglutamate Aβ3−42 (AβpE3−42) and Aβ4−42 peptides are known to be highly abundant in the brain of Alzheimer’s disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aβ, suggesting that these Aβ isoforms play an important role in the pathogenesis of AD. Hence, in the current work, the in vivo effect of the combination of AβpE3−42 and Aβ4−42 on ongoing AD-related neuron loss, pathology, and neurological deficits was investigated using the newly generated TBA42/Tg4-42 mouse model. The TBA42/Tg4-42 mouse model was generated by crossing the established TBA42 and Tg4-42 models expressing AβpE3−42 and Aβ4−42, respectively. TBA42/Tg4-42 mice exhibited an accelerated loss of CA1 pyramidal neurons in comparison to homozygous single transgenic TBA42 and Tg4-42 mice, which nicely correlated with prominent intraneuronal Aβ accumulation in the CA1 region. Additionally, reduced anxiety levels and enhanced motor deficits were determined in TBA42/Tg4-42 mice in an age-dependent manner. The sensory-motor deficits strongly correlated with the robust intracellular Aβ accumulation within motor neurons and extracellular Aβ deposition in the spinal cord. Despite the massive neuron loss in the CA1 region, no deficits in working and spatial refence memory could be detected in TBA42/Tg4-42 mice at any ages studied. Furthermore, aggregation kinetics analysis indicates that under physiological conditions, when AβpE3-42 and Aβ4-42 peptides are combined, aggregation propensity is enhanced. These observations confirm the importance of AβpE3-42 and Aβ4-42 in the progression of AD and suggest a possible in vivo interaction between these two N-truncated Aβ peptides. One of the key pathological hallmarks of AD is the extracellular aggregation and deposition of Aβ in the form of plaques. However, the presence of Aβ plaques has also been found in cognitively normal subjects. Additionally, accumulated evidence from AD brains suggests that the levels of soluble Aβ oligomers correlate better with the risk and severity of the disease than insoluble amyloid plaques. In order to study the association between soluble Aβ oligomers and insoluble fibrillar plaques in vivo, the 5XFAD and the Tg4-42 mouse models were crossed to produce the novel FAD4-42 model. The 5XFAD model exhibits early and aggressive amyloid pathology, while the Tg4-42 develops age-dependent CA1 neuron loss and does not develop amyloid plaques. FAD4-42 mice showed an increased amyloid burden compared to 5XFAD mice at 3 months of age. However, at 12 months of age, no differences could be detected between 5XFAD and FAD4-42 mice. Furthermore, no neuron loss in the CA1 region of the hippocampus was observed in the FAD4-42 model at 3 or 12 months of age. These results indicate that soluble Aβ4-42 binds to amyloid plaques resulting in a reduction of Aβ4-42 toxicity, suggesting a potential protective effect of amyloid plaques against soluble toxic Aβ oligomers.
Keywords: Alzheimer’s disease; N-truncated Aβ; Pyroglutamate Aβ; Neuron loss; Intraneuronal Aβ
 
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