Modelling Alzheimer's disease in multiple transgenic mice

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Alzheimer's disease (AD) pathology involves amyloid plaques and neurofibrillary tangles.
• Transgenic mouse models are crucial for studying AD pathogenesis.
• Current models often fail to replicate all aspects of AD, particularly tangle formation.

Purpose of the Study:

• To investigate the development of AD-related phenotypes in transgenic mice overexpressing mutant amyloid precursor protein (APP).
• To examine the impact of co-expressing APP with Presenilin 1 on amyloid pathology.
• To assess the role of apolipoprotein E4 (ApoE4) and tau overexpression in neurodegeneration.

Main Methods:

• Neuronal overexpression of the London mutant APP in transgenic mice.
• Generation of double-transgenic mice (APP/London x Presenilin 1).
• Overexpression of human apolipoprotein E4 (ApoE4) or human tau in central neurons.

Main Results:

• APP/London mice exhibited early AD-like symptoms (behavioral, cognitive deficits) preceding amyloid plaque formation.
• Amyloid plaques and increased beta-amyloid (A beta)40/42 levels were observed in aged APP/London mice.
• APP/London x Presenilin 1 mice showed accelerated amyloid plaque development by 6 months.
• ApoE4 or tau overexpression led to severe axonopathy, nerve/muscle degeneration, and premature death, but not neurofibrillary tangles.

Conclusions:

• Amyloid plaque formation is temporally dissociated from early AD-like phenotypes in APP/London mice.
• Current transgenic models, including those with APP, Presenilin 1, ApoE4, or tau, do not fully recapitulate AD pathology, specifically the absence of neurofibrillary tangles.
• Further research is needed to understand tau phosphorylation and cellular signaling pathways to implement tangle pathology in AD models.