Antibodies in cerebrospinal fluid of some Alzheimer disease patients recognize cholinergic neurons in the rat central nervous system.

Abstract

The etiology of Alzheimer disease is unclear. However, immunological aberrations have been suggested to be critical factors in the pathogenesis of this neurodegenerative disease. This study was carried out to investigate if cerebrospinal fluid (CSF) from Alzheimer disease patients contains antibodies that recognize specific neuronal populations in the rat central nervous system. The results indicate that in a subgroup of patients this is indeed the case. The antibodies reported in this study have the following properties: (i) they recognize neuronal populations and components in the medial septum and spinal motor neurons in rats perfused with a mixture that fixes small neurotransmitter molecules; (ii) adsorption of the patient CSF with staphylococcal protein ASepharose and using a polyclonal antiserum against human IgG3 indicates that the immunocytochemical reaction in these brain regions is mainly due to the subclass IgG3; and (iii) the CSF immunocytochemical reaction is blocked by preincubation of the sections with a rabbit anti-acetylcholine antiserum. These results provide evidence that antibodies in the CSF of some, but not all, Alzheimer disease patients recognize acetylcholine-like epitopes in cholinergic neurons in the rat central nervous system. Alzheimer disease (AD) is a neurodegenerative disorder characterized by loss of memory, perception, reasoning, orientation, and judgement. The impairment of intellectual function has been correlated with abnormal morphological phenomena, the most prominent being neurofibrillary tangles and neuritic plaques as well as the loss of cholinergic presynaptic markers (1)(2)(3)(4) (8). Clinical examination confirmed dementia of mild to moderate degree. The patients had no symptoms corresponding to other neurological disorders. The CSF samples (12 ml) were collected on ice, gently mixed to avoid gradient effects, centrifuged to remove cells, divided into 2-ml aliquots, and immediately frozen at -20'C without preservatives. At the time of sampling the patients were not receiving pharmacological treatment. A more detailed description of patient history will be given elsewhere.Immunocytochemical Approach. Three male rats (SpragueDawley) were perfused with a mixture of 5% (wt/vol) glutaraldehyde and allyl alcohol (1 M) in a sodium cacodylate buffer (0.5 M, pH 12) (9, 10). After thorough washing in Tris base (0.5 M) containing 1% sodium metabisulfite (adjusted to pH 7.6 with concentrated sodium hydroxide) the brains were rinsed overnight in the same buffer containing 10% sucrose and then frozen with compressed CO2 gas. Brains were sectioned (10 ,um) in a cryostat. Serial frozen sections of the medial septum (MS) and vertical limb of the diagonal band (VDB), or of the spinal cord, were mounted on gelatin-coated glass slides and incubated with 2% normal goat serum for 30 min. The serial sections of the MS or spinal cord were incubated overnight either with rabbit antiserum to acetylcholine (AcCho) (9) (1:500 or 1:200) or with the CSF from the eight AD patients (1:1) dil...

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