Altered apolipoprotein D expression in the brain of patients with Alzheimer disease

Abstract

The etiology of late-onset Alzheimer disease is poorly understood. Predisposing factors such as the apolipoprotein E4 allele, as well as protective factors (e.g., antioxidants) have been proposed to play a role in the disease's process. A search for predisposing factors contributing to sporadic late-onset Alzheimer disease was initiated using the differential display technique. RNA expression profiles of the entorhinal cortex and the cerebellum of Alzheimer-diseased and normal patients were compared. The entorhinal cortex is the first brain region to accumulate neurofibrillary tangles during disease progression, whereas the cerebellum is spared. In the Alzheimer cases of this study, one signal showing preferential expression in the entorhinal cortex corresponded to the apolipoprotein D gene. This preferential expression might be genuine at the RNA level as suggested by the in situ hybridization method used. In addition, immunohistochemical experiments showed higher percentages of Apolipoprotein D reactive pyramidal neurons in the entorhinal cortex and region 1 of Ammon's horn in diseased patients. This increase correlated with the number of neurofibrillary tangles in Alzheimer as well as in normal patients. Colocalization of Apolipoprotein D proteins and neurofibrillary tangles in the same neuron was rare. Thus, these results suggest that in Alzheimer disease and aging, apolipoprotein D gene expression is increased in stressed cortical neurons before they possibly accumulate neurofibrillary tangles.

Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder

“…For example, apoD levels have been shown to be elevated in brains of patients with other neurological disorders, such as Alzheimer's disease, cerebrovascular disease, motoneuron diseases and meningoencephalitis, and presumably these patients had not been exposed to antipsychotic drugs. [13][14][15] Some behaviorally disturbed Alzheimer's patients may have received antipsychotic drug treatment; however, we also observed increases in apoD expression in a mouse model of Alzheimer's disease and these mice were not treated with antipsychotic drugs. 50 Together, these findings would argue against the changes in apoD reported in this study being simply an effect of antipsychotic drugs.…”

“…The increase of apoD expression that has been observed in response to diverse neuropathologies may represent a nonspecific response to cellular injury. However, given the distinct sites of apoD upregulation observed after CNS insult in the rodent studies and the regional specificity of apoD induction observed in human disease, [8][9][10][11][13][14][15] we hypothesize that apoD represents a response to a pathological process in affected brain regions. Given its role as a lipidbinding protein and member of the lipocalin family of transport proteins, apoD may be involved in the binding of steroids or fatty acids released upon CNS insult, or the transport of lipid molecules necessary for dendritic or synaptic remodeling in response to neuropathology.…”

“…Increases in apoD immunoreactivity have been reported in both cerebrospinal fluid (CSF) and brains of Alzheimer's patients, and in the CSF of patients with cerebrovascular disease, motoneuron diseases and meningoencephalitis. [13][14][15] Additionally, increased intrathecal production of apoD has been observed in multiple sclerosis. 16 Together these data suggest that apoD is increased in response to neurological stress, because of either clinical or mechanical lesioning or active disease pathology.…”

Evidence for defective retinoid transport and function in late onset Alzheimer's disease

“…Apolipoprotein D expression is regulated by RARA (55), and increased in stressed neurons of AD patients (56), as well as in normal aging, before the accumulation of neurofibrillary tangles (57). We suggest that the increased expression may be the result of feedback mechanisms dependent on the reduced amounts of retinol in aging individuals (58).…”

Co-administration of Ciliary Neurotrophic Factor with Its Soluble Receptor Protects against Neuronal Death and Enhances Neurite Outgrowth

“…This possibility received support from the microarray analyses, which indicated that, compared with CNTF alone, Complex differentially affected the expression of 47 genes, several of which are known to contribute to neuroprotection (e.g. Apod (47), Dcn (48), Dspg3 (49), Mdm2 (50), Plg (51), Sgk2 (52), and Tnfrsf18 (53)) and/or neuronal development (e.g. Apod (54), Dcn (54,55), Dspg3 (49,56), Plg (57), and Plxnb3 (58)).…”