Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

Abstract

The epsilon 4 allele of the human apolipoprotein E gene (ApoE4) constitutes an important genetic risk factor for Alzheimer's disease. Recent experimental evidence suggests that human ApoE is expressed in neurons, in addition to being synthesized in glial cells. Moreover, brain regions in which neurons express ApoE seem to be most vulnerable to neurofibrillary pathology. The hypothesis that the expression pattern of human ApoE might be important for the pathogenesis of Alzheimer's disease was tested by generating transgenic mice that express human ApoE4 in neurons or in astrocytes of the central nervous system. Transgenic mice expressing human ApoE4 in neurons developed axonal degeneration and gliosis in brain and in spinal cord, resulting in reduced sensorimotor capacities. In these mice, axonal dilatations with accumulation of synaptophysin, neurofilaments, mitochondria, and vesicles were documented, suggesting impairment of axonal transport. In contrast, transgenic mice expressing human ApoE4 in astrocytes remained normal throughout life. These results suggest that expression of human ApoE in neurons of the central nervous system could contribute to impaired axonal transport and axonal degeneration. The epsilon 4 allele of the apolipoprotein E (ApoE) gene is associated with Alzheimer's disease (AD), affecting the onset of the disease in an allele dose-dependent manner. 1,2 ApoE4 is associated with increased plaque load in AD 3-5 and early onset of neurofibrillary changes. 6 ApoE4 has also been implicated in poor neurological recovery after head injury, cerebral hemorrhage, and cardiac bypass surgery. [7][8][9][10][11][12] In addition, ApoE4 was suggested to act as a risk factor for bulbar-onset amyotrophic lateral sclerosis, for Pick's disease, corticobasal degeneration, and progressive supranuclear palsy (characterized by protein Tau-related cytoskeletal pathology), and for inclusion body myositis, although contradictory results have been found. [13][14][15][16][17][18][19] Epidemiological data do not provide evidence for a direct role of ApoE in central nervous system disorders, and its mechanism of action within the central nervous system is not clear. Originally, it was thought that ApoE present in neurons originated only from endocytosis. 20 -22 Numerous cell culture experiments demonstrated receptor-mediated uptake of ApoE as well as effects on neurite outgrowth and cell-morphology. [23][24][25][26][27][28][29] However, more and more evidence indicates that intraneuronal ApoE might also originate from synthesis by neurons. In situ hybridization of brain sections of transgenic mice expressing genomic fragments containing the entire human ApoE locus, including its promoter sequences, revealed expression in neurons, besides astrocytes. 30 -32 Human neuroblastoma cells were shown to synthesize both ApoE mRNA and protein. 33,34 Moreover, in situ hybridization of human brain sections conclusively demonstrated ApoE mRNA in neurons. 35 Taken together these results suggest that besides its well-known synthesis...

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

“…Disrupted transport has been shown in AD (Cash et al, 2003;Praprotnik et al, 1996;Richard et al, 1989;Terry, 1996) and also amyotrophic lateral sclerosis (Williamson and Cleveland, 1999), however relatively few studies have examined this aspect of the disease (Kasa et al, 2000). Nonetheless, numerous factors implicated in AD including oxidative stress (de la Monte et al, 2000;Perry and Smith, 1997;Smith et al, 1995), APO e (Tesseur et al, 2000), and APP-L (Torroja et al, 1999) have all been shown to affect axonal transport. The observation that AbPP can serve as a kinesin cargo receptor (Kamal et al, 2000(Kamal et al, , 2001 as well as the inhibition of kinesin-dependent transport by tau overexpression (Ebneth et al, 1998;Stamer et al, 2002) should not be overlooked.…”

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

“…Features of AD pathology in these animals include reduced numbers of presynaptic terminals in mice expressing apoE4 with (54,64) or without (53,66,68) expression of human amyloid precursor protein (APP), increased plaque deposition in apoE4 mice expressing APP (64), increased phosphorylation of tau (65)(66)(67), impaired learning and memory (55,69), and altered long-term potentiation (77).…”

“…Furthermore, the N-terminal domain of apoE3 is responsible for irreversibly binding to tau through the microtubule-binding repeat regions (56,152). Increased phosphorylation of tau has been observed in transgenic mice expressing human apoE4 in neurons but not in mice expressing apoE4 in astrocytes (65,66,129). Thus, apoE4 may have a neuron-specific effect on tau phosphorylation.…”

Deciphering the mechanism underlying late-onset Alzheimer disease

“…Such an outcome could explain why this organelle has a fragmented and atrophic morphology in neurons of patients with AD. 98 Interestingly, over expression of APOE ε4, as well as mutations in PS1 and APP, also affect tau phosphorylation, axonal transport, and neuronal dystrophy [99][100][101][102] in an Aβ-independent manner, which suggests a possible converging process underlying the familial and sporadic forms of the disease.…”