Severe Motor Neuron Degeneration in the Spinal Cord of the Tg2576 Mouse Model of Alzheimer Disease

Abstract

The transgenic mouse Tg2576 is widely used as a murine model of Alzheimer's disease (AD) and exhibits plaque pathogenesis in the brain and progressive memory impairments. Here we report that Tg2576 mice also have severe spinal cord deficits. At 10 months of age, Tg2576 mice showed a severe defect in the hindlimb extension reflex test and abnormal body trembling and hindlimb tremors when suspended by the tail. The frequency and severity of these abnormalities were overt at 10 months of age and became gradually worsened. On the foot-printing analysis, Tg2576 mice had shorter and narrower strides than the non-transgenic control. Histological analyses showed that neuronal cells including cholinergic neurons in the lumbar cord of Tg2576 mice were severely reduced in number. At 16 months of age, Tg2576 mice showed high levels of amyloid-beta accumulation in the spinal cord. Consistent with this, Tg2576 mice showed that lipid peroxidation levels were increased and mitochondrial metabolic activity were significantly reduced in the spinal cord. Administration of curcumin, a natural compound that has antioxidant properties, notably reversed motor function deficits of Tg2576 mice. The enhanced lipid peroxidation and neuronal loss in the lumbar cord was also partially suppressed by curcumin. Electron microscopic analysis revealed that the sciatic nerve fibers were severely reduced in number and were demyelinated in Tg2576 mice, which were partially rescued by curcumin. These results showed that Tg2576 mice display severe degeneration of motor neurons in the spinal cord and associated motor function deficits.

Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

“…For example, Aβ accumulation has been found in the spinal cords of patients with both the familial and sporadic forms of ALS (48) as well as in the skin and muscles of ALS patients (49, 50), and biomarkers linked to the amyloid cascade have been found in the CSF of patients with ALS and FTD (49). In addition, increased APP expression has been observed in spinal cord motor neurons in experimental models in the early stages of ALS (51–54), and some experimental models of AD have displayed extracellular Aβ plaques in motor neurons, similar to those found in humans with AD (55). Likewise, increased Aβ expression has been found in affected motor neurons and the surrounding glial cells in SOD1 G93A mouse models; genetic ablation of APP in these mice reduces motor neuron degeneration (56).…”

Cholinergic Nerve Differentiation of Mesenchymal Stem Cells Derived from Long-Term Cryopreserved Human Dental Pulp In Vitro and Analysis of Their Motor Nerve Regeneration Potential In Vivo

“…Some methods for neuronal cell differentiation from MSCs were introduced via transgenic technology or using a cocktail induction medium, such as retinoic acid and growth factors, β-mercaptoethanol and butylated hydroxyanisole, or 5-azacytidine and growth factors [25,26,27]. However, the cholinergic nerve differentiation potential of MSCs is yet to be broadly studied, despite the loss of cholinergic neurons resulting in Alzheimer’s disease and motor neuron degeneration [28]. …”

Modeling mitochondrial dysfunctions in the brain: from mice to men

“…The popular Tg2576 murine model of Alzheimer’s disease, generated by over-expressing a mutated form of human AβPP (K670M/N671L), is often used in studying AD because it exhibits plaque formation in the brain and progressive memory impairments, similar to those suffering AD (Seo et al 2010). More specifically, cognition testing in these animals reveals that they show deficits in the Morris water maze, the Y-maze and several kinds of passive avoidance paradigms (King and Arendash 2002).…”

“…Also, unlike many of the animal models named previously, this particular model is widely commercially available and therefore easily obtainable for those wanting an in vivo AD model. The AD-like pathology shown by these animals is thought to be due to the transgenic expression of a mutant form of human AβPP in the brain, which may also have effects on neurons in the spinal cord, which may also partially account for the motor dysfunctions seen in these animals (Seo et al 2010). …”