|7. Animal Model: APP/PS1 Expression||Alzheimer|
In rare cases, Alzheimer's disease (AD) is caused by genetic mutations in one of three genes: APP, PSEN1 and PSEN2. The APP gene encodes amyloid precursor protein (APP), PSEN1 encodes Presenilin 1 (PS1) and PSEN2 encodes Presenilin 2 (PS2). Individuals with these mutations may develop AD early in their life, around 40 years of age. This type of AD is called familial AD or early-onset AD. In most cases, AD is not associated with these mutations and usually begins after 60. This type of AD is termed sporadic AD.
Presenilin is the γ-secretase involved in the generation of Aβ peptides from APP (see Chapter 4). Mutations in the familial AD were found to increase the production of Aβ42 (Mann et al., 2001). Although familial AD is rare, it has motivated researchers to use the transgenic mice (or other animals) with mutant APP and/or PSEN1. In the transgenic animal model, foreign genes (e.g., mutant APP and PSEN1) are introduced into the animal by recombinant DNA technology, producing encoded proteins through the process of gene expression.
Since the expression of mutant APP/PS1 can produce more Aβ42 peptides, one may expect that the transgenic animal model should exhibit similar results to direct Aβ42 injection (see Chapter 6). In fact, they have profound differences.
While Aβ injection causes little damages in the axon, significant axonopathy was observed in transgenic mice and Drosophila (Stokin et al., 2008). According to the Amyloid Cascade Hypothesis, which posits that neurotoxicity in AD is primarily caused by Aβ oligomers, the axonal impairment should be exacerbated by Aβ injection. Surprisingly, an increase in the Aβ42/Aβ40 ratio, as well as enhanced deposition of Aβ peptides, actually suppress the axonal defects in transgenic mice and Drosophila (Stokin et al., 2008)!
The transgenic animal model also revealed that alterations in brain myelination patterns at the perforant pathway appeared prior to amyloid plaque and neurofibrillary tangles (Desai et al., 2009). The perforant pathway is a principal input to the hippocampus from the entorhinal cortex. Its pathological changes in AD brains were first reported by Hyman et al. in 1986.
Hyperexcitability is an early sign of Alzheimer's disease (Dickerson et al., 2005; Putcha et al., 2011). It has also been observed in the transgenic mouse model (Wesson et al., 2011; Bezzina et al., 2015). By contrast, in the animal model using Aβ oligomer injection, neuronal excitability is reduced due to AMPAR endocytosis, or more severely, synapse loss (see Chapter 6). As mentioned above, Aβ injection into the APP/PS1 transgenic mice suppresses the axonal defects. These results suggest that the neurotoxicity may originate from hyperexcitability.
Then, what causes hyperexcitability? The next chapter will present evidence that the answer may lie in the protein, Ankyrin-G, whose expression level is reduced in the APP/PS1 transgenic mice (Sun et al., 2014). Injection of Ankyrin-G into the APP transgenic mice reduces β-amyloid pathology (Santuccione et al., 2013).
Author: Frank Lee