Animal Model of Aluminum-Induced Alzheimer’s Disease
7.4 The Similar Features in Al-Maltolate-Treated Rabbits with AD Patients
7.4.1 Neurofibrillary Degeneration
After intraventricular administration of Al maltolate to rabbits, widespread neurofi- brillary degeneration was found in pyramidal neurons of the isocortex and allocor- tex, nerve cells of the brain stem and spinal cord, and projection neurons of the diencephalon, especially the perikarya and proximal neurites [26]. When the
intraventricular administration of Al maltolate is longer than 12 weeks, NFAs appeared in the pyramidal neurons and the oculomotor complex of the occipital cortex. Compared with motor neuron disease and the senile dementia of the Alzheimer type, widespread argyrophilic NFAs are seen in a number of brain regions in Al-treated aged and young rabbits. Compared with the less water-soluble Al compounds, intraventricular Al maltolate produces similar but more widespread degeneration of projection-type neurons. In addition, compared with the young rab- bits, the aged animals are damaged to a much wide range by the Al. This may be related to an active mechanism which is involved in suppressing Al-maltolate toxic- ity and is decreased in the aging rabbit brain.
NFAs are observed mostly in the superior and the inferior hippocampus, lateral and inferior cerebral cortices, the superior cortex, and the stratum pyramidale subic- ulum [23, 30]. NFD is observed in cerebral cortical neurons and in the inferior seg- ment of the hippocampus of aged Al-treated rabbits. NFD induced by intracisternal Al administration appeared mostly in the medulla and upper spinal cord. Compared with the aged rabbits treated with Al maltolate, the young rabbits are less affected in brain regions. NFTs were observed by confocal imaging of axons in hippocampal neurons (Fig. 7.2) from Al-treated aged rabbits [19].
Using a method of computer-controlled electron beam X-ray microanalysis and wavelength dispersive spectrometry, Gamito et al. successfully got the imaging of Al in the hippocampus NFT of Guamanian patients [31]. The elemental images showed that Al is distributed in cell bodies and axonal neurons which display NFT either. The result that Al deposits occur within the same NFT-bearing neurons and the result that compared with control case, no obvious increase of Al concentrations was imaged in non-NFT-bearing neurons in the pyramidal cell layer indicated that Al maybe involved in NFT formation.
In addition, Savory and his co-workers made many researches on the quantita- tion of Al in the brain and neurofilament protein expression and phosphorylation effected by Al [32]. The accumulation of Al in different brain regions of aged rab- bits treated with Al maltolate was detected, yielding about 10 μg/g dry tissue in the
Fig. 7.2 NFT in axons imaged in a single neuron from hippocampal region of Al-treated aged rabbits
brain and spinal cord but only 2.1 μg/g dry tissue in the lumbar cord. The result also showed that in perikarya and proximal neurites of neurons of the lumbar and sacral cord areas, argyrophilic tangles were detected either. But, immunoblot studies showed negative changes in three neurofilament protein isoforms, the total phos- phate content of these proteins, and the genes encoding for the 200 and 68 KDa neurofilament proteins. These results provided new evidence for the involvement of Al in AD.
The neurofilament protein phosphorylation in aged rabbits treated by Al malto- late was different from the AD patient. In Al-maltolate-treated aged rabbits, neuro- filament proteins like tau, a-1-antichymotrypsin, and ubiquitin are unphosphorylated, while in AD neurofilament protein is hyperphosphorylated [27, 29]. Using different kinds of monoclonal antibodies which can recognize nonphosphorylated and phos- phorylated tau, quantity of the abnormally phosphorylated tau present in these NFAs are detected. The results showed that both nonphosphorylated and phosphor- ylated tau are displayed.
From the thermodynamic view, cytoskeletal protein hyperphosphorylation and the associated negative charges may result in the destabilization of these aggregates.
So, a hypothesis is made that phosphorylation of cytoskeletal proteins promotes the formation of the NFAs particularly in AD [28]. Thus, it is also reasonable to propose that both in AD and in experimental Al-maltolate-induced NFAs, some positively charged substance such as metal ions promotes the formation and stability of the NFAs. In the experimental Al-maltolate-induced NFAs, Al may play the role of one promoter [33].
Although the biochemical and morphologic features between NFTs induced by Al in rabbits and the neurofibrillary tangles of AD are not fully same at both gross and ultrastructural levels, there are many similarities displayed. First of all, the dis- tribution of both tangles is different, while both types of tangles are shown in the cortex and hippocampus [11, 34]. Tangles induced by Al are found in the perikaryon and proximal parts of the dendrites and axon in the rabbits [35, 36], while tangles of AD are found throughout the axons including the terminals and throughout the neu- ron including the entire length of the dendrites. Secondly, the protofilament building blocks of tangles are also different in the diameter. Tangles induced by Al are 2.0 nm, while those of AD are 3.2 nm. Finally, the biochemical composition of tangles is not the same at all. The peptide composition of Al-induced tangles is chiefly neurofilament protein. In contrast, the paired helical filaments of AD tangles are much more complicated, composed of three proteins at least such as hyperphos- phorylated tau, a microtubule-associated protein, and ubiquitin. Similar results about Al-induced tangles in rabbits and those of AD were reported by Klatzo et al.
[4]. In addition, if the tissue is treated with silver staining, Al-induced tangles and AD pathology appeared similar [35, 37, 38].
The similarities and differences between Al-maltolate-induced tangles in New Zealand aged white rabbits and the neurofibrillary lesions of AD are summarized by Bharathi et al. [39] in Table 7.2.