Toxicity of Amyloid beta (Aβ) in Alzheimer's Disease

澱粉樣蛋白β(Aβ) 在阿爾茨海默病中的毒性

Student thesis: Master's Thesis

View graph of relations

Related Research Unit(s)

Detail(s)

Awarding Institution
Supervisors/Advisors
Award date10 Sep 2018

Abstract

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by a progressive memory loss and cognitive impairment. Pathologically, this disease has been regarded by the extracellular accumulation of amyloid beta (Aβ) peptides in plaques. AD is associated with the formation of plaque and tangle in brain, was thought that accumulated Aβ peptides accelerate the progression of AD by increasing the number of neuronal loss and promoting neurodegeneration. Recently, it is believed that accumulation of Aβ is the outcome of neurodegeneration in AD that is neurotoxic. However, it remains to be elucidated whether the accumulation of Aβ is a cause or a consequence of AD. To study toxicity of Aβ, we used TgCRND8 (Tg) mice which express human mutant APP (Amyloid Precursor Protein). Interestingly, what we observed was several young Tg mice died early, around age of 3 weeks or even earlier. Based on this, we hypothesized that Aβ accumulation has a neurotoxic effect, a cause of neurodegeneration, in in the central nervous system. To test this, we have conducted immunohistochemistry (IHC) with antibodies against Aβ40 and hypophosphorylated neurofilament heavy chain (SMI-32, a marker of neurodegeneration) in mouse brains from wild-type and Tg mice. When young Tg mice died early, ~3 weeks, we harvested the brain and compared the pathological patterns of Aβ accumulation with the adult Tg mice. We observed Aβ accumulation in 3-wks-old Tg mouse brain which is normally observed in Tg mouse brain after 12 wks. After that, SMI-32 staining result showed hypophosphorylated neurofilament in both young and adult Tg mice brain. This indicates the occurrence of neurodegeneration in these Tg mice. iii

These data suggest that Aβ accumulation is related with the death of young Tg animals through neurodegeneration. To further examine whether Aβ accumulation induces cell death in the brain, we examined apoptotic cell death by IHC with anti-Annexin V antibody which detects phosphatidylserine residues on the surface of cell, an early event in apoptosis. We found no significant apoptotic cell death in Tg mice compared to that in wild-type mice. This result suggests that Aβ accumulation does not cause significant cell death in the brain of AD through apoptosis.