Geon 6. Animal Model: Aβ Injection Alzheimer

Rats and monkeys are often used as model systems to investigate the detailed mechanisms of human diseases. Some great insights have been revealed on the role of beta amyloid (Aβ) in Alzheimer's disease (AD).

Injection of Aβ Fibrils

As described in Chapter 4, two or more Aβ peptides may combine to form a small oligomer. Aβ fibrils are the larger entities consisting of Aβ oligomers. They may further aggregate to become the amyloid plaque. To see if the plaque is the cause of neurotoxicity in AD, researchers (Geula et al., 1998) injected fibrillar Aβ at plaque-equivalent concentrations into the cerebral cortex of monkeys or rats. The results were age-dependent. Only the aged monkeys or rats exhibited some degree of neurotoxicity that led to neuronal loss. No significant toxicity was observed in young monkeys or rats.

These results suggest that the amyloid plaque is not the main cause of neurotoxicity in AD (Yankner and Lu, 2009). In fact, the aggregation of oligomers into fibrils or plaque has beneficial effects, because small Aβ oligomers are much more toxic.

Injection of Aβ Oligomers


Figure 6-1. Schematic diagram outlining mechanisms of Aβ oligomer-induced synaptic dysfunction. See text for details. [Modified from Tu et al., 2014]

Injection of Aβ oligomers causes localized Ca2+ elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines (Zempel et al., 2010). The mechanism is illustrated in Figure 6-1. The Aβ oligomer can bind to α7 nicotinic acetylcholine receptors in the presynaptic axon terminal, resulting in the release of glutamate, which in turn activates synaptic NMDA receptors (sNMDARs) in the postsynaptic neuron, leading to Ca2+ elevation in the postsynaptic spine.

Alternatively, the Aβ oligomer may bind to α7 nicotinic acetylcholine receptors in the glial cell (astrocyte and microglia), resulting in the release of glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs). The Ca2+ elevation can also be induced through this pathway (Talantova et al., 2013).

Ca2+ overload is toxic to the neuron because it can activate a variety of Ca2+-dependent enzymes such as the protein phosphatase calcineurin/PP2B. Activation of the phosphatase may cause cofilin to sever actin filaments, leading to dendritic spine loss (Tu et al., 2014). Calcineurin may also stimulate AMPAR endocytosis which, however, is not entirely harmful, since removal of AMPAR from the synapse reduces excitability and Ca2+ influx.

Another important toxic pathway involves calpain and cyclin dependent kinase 5 (Cdk5) (Seo et al., 2014). Cdk5 is normally activated by the protein p35 or p39. High Ca2+ concentration activates calpain which cleaves p35 to p25, forming a more stable yet hyperactive Cdk5/p25 complex (Shukla et al., 2011). Kinase is a type of enzyme that catalyzes protein phosphorylation. Cdk5 may target the Tau protein, resulting in Tau hyperphosphorylation (Kimura et al., 2014).

Hyperphosphorylated Tau cannot bind on microtubules. This may cause Tau mislocalization to dendrites (Li et al., 2011). The missorted Tau may trigger microtubule severing by TTLL6 and spastin (Zempel et al., 2013). Synapses will be lost without intact microtubules to transport necessary components. On the other hand, neurofibrillary tangles can be formed by the aggregation of hyperphosphorylated Tau proteins.

Failure of the "Amyloid Cascade Hypothesis"

Between 1990 and 2010, Aβ was thought to be the primary cause of AD. Many drugs were developed on the basis of the "Amyloid Cascade Hypothesis" (Hardy and Higgins, 1992). Unfortunately, "to date, all AD clinical trials based on Aβ as a therapeutic target have failed" (Gong et al., 2010). This led to a scientific meeting (2011) that gave attendees the opportunity to openly debate the proposal "the amyloid cascade hypothesis has misled the pharmaceutical industry".

Aβ injection affects mainly dendrites, not the axon. However, in a transgenic animal model (see next chapter), axonal defects at the perforant path preceded amyloid plaque and neurofibrillary tangles (Desai et al., 2009). Perforant path is the principal input to hippocampus from entorhinal cortex where AD is initiated. Chapters 8-11 will explain why this area is the most vulnerable to develop AD.


Author: Frank Lee
First published: May 23, 2015
Last updated: June 16, 2015