The influence of neprilysin on the pathogenesis of sporadic Alzheimer’s disease

by Karen Annette Hornung
Doctoral thesis
Date of Examination:2024-05-23
Date of issue:2024-05-16
Advisor:Prof. Dr. Oliver Wirths
Referee:Prof. Dr. Oliver Wirths
Referee:Prof. Dr. Tiago Outeiro
Persistent Address: http://dx.doi.org/10.53846/goediss-10498

 

 

Files in this item

Name:Dissertation-Hornung-eDiss.pdf
Size:3.27Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

The approach of this study was to examine the influence of neprilysin on the pathogenesis of sporadic Alzheimer’s disease. In three parts, this study combined standard histologic, immunohistochemical and in-vitro proteolysis experiments. The Tg4-42 mouse model represents an established model for the sporadic Alzheimer’s disease. Bred with neprilysin-gene knock out mice, Tg4-42/NEP-/- were generated to be compared to wildtype, NEP-/- and Tg4-42 mice. To examine age-dependent effects of neprilysin deficiency, 3-month-old and 12-month-old animals were selected for each group. In the first part, neuron numbers of the hippocampal CA1 area were quantified by unbiased design-based stereology. Results revealed significant neuron loss in young neprilysin-deficient Tg4-42 mice whereas neprilysin deficiency did not alter neuron number of aged Tg4-42 mice. In the second part, Aβ4-40/4-42-immunoreactivity was measured on imaged brain sections and demonstrated a significantly enhanced Aβ load in young but not in aged Tg4-42/NEP-/- mice compared to age-matched Tg4-42 mice. In the third part, SDS-PAGE was applied to visualize and qualify efficient in-vitro degradation of Aβ4-40 and Aβ4-42 by neprilysin. In conclusion, neprilysin deficiency is suggested to aggravate neurodegeneration which is reflected in neuron loss and increased Aβ load. Aβ4-40 and Aβ4-42 were demonstrated to be substrates of neprilysin. Especially in early stages of amyloidogenesis, an aggravation of neuropathological alterations upon neprilysin deficiency was observed.
Keywords: Alzheimer's disease; neprilysin; sporadic Alzheimer's disease; mouse model; tg4-42; intraneuronal amyloid-beta; transgenic mice; neuron loss
 
Statistik