Aluminum-induced Neurofibrillary Degeneration Research Articles

Interaction of aluminum with paired helical filament tau is involved in neurofibrillary pathology of Alzheimer's disease.

Since the first reports of aluminum-induced neurofibrillary degeneration in experimental animals, extensive studies have been performed to clarify the role played by aluminum in the pathogenesis of Alzheimer's disease (AD). Additional evidence implicating aluminum in AD includes elevated levels of aluminum in the AD brain, epidemiologic data linking aluminum exposure to AD, and interactions between aluminum and protein components in the pathologic lesions of AD, i.e., neurofibrillary tangles (NFTs) and senile plaques. As most of this evidence is circumstantial and some of it is not consistent in all reports, the role of aluminum in the pathogenesis of AD has remained controversial. However, the interaction of aluminum with altered forms of tau in the paired helical filaments (PHFs) of neurofibrillary lesions is highly likely to contribute to the formation of NFTs because (1) aluminum and abnormally phosphorylated tau (known as PHF tau) are colocalized in NFTs, and (2) aluminum is known to preferentially interact with such phosphorylated proteins. Recently, it was demonstrated that aluminum binds selectively to PHF tau, induces PHF tau to aggregate, and retards the in vivo proteolysis of PHF tau. These data suggest that aluminum could serve as a cofactor in the formation of NFTs by interacting with PHF tau. This review summarizes the current understanding of how aluminum might contribute to the formation of neurofibrillary lesions from PHF tau in neurons of the AD brain.

Aluminum-induced neurofibrillary degeneration - A model system: K.R. Fry, A.L. Chapman, K.A. Jansa and C.B. Watt. Center for Biotechnology, Baylor College of Medicine, The Woodlands, TX, USA 77381

Aluminum-induced neurofibrillary degeneration - A model system: K.R. Fry, A.L. Chapman, K.A. Jansa and C.B. Watt. Center for Biotechnology, Baylor College of Medicine, The Woodlands, TX, USA 77381

The rabbit retina: A long-term model system for aluminum-induced neurofibrillary degeneration

Aluminum (Al) was injected into the rabbit eye as a potential long-term model system for Al-induced neurofibrillary degeneration (NFD). Neurofibrillary tangles made up of 10 nm phosphorylated neurofilaments were observed in a subpopulation of retinal ganglion cells, located primarily in the peripheral retina. The distribution of affected cells suggested a differential susceptibility of ganglion cells to Al intoxication. Importantly, none of the animals demonstrated any of the central neurological dysfunctions characteristic of previous Al intoxication models. The retinal model should allow for long-term studies of Al intoxication and its potential relationship to neurofibrillary degenerative disorders such as Alzheimer's disease.

Disrupted retention of the classically conditioned nictitating membrane response in the aluminum-intoxicated rabbit using electrical stimulation of the brain as a conditioned stimulus

Rabbits were classically conditioned to emit an eyeblink conditioned response (CR) to electrical stimulation (ESB) of the medial geniculate nucleus (MGN) paired with a corneal air puff until they attained a criterion of two consecutive days of greater than 90% CRs. They then received intraventricular injections of 1% AlC1 3, HCL, or normal saline. Ten days postinjection, each animal underwent a retention test consisting of 50 ESB alone presentations. Whereas all saline and HCL animals gave at least 90% CRs during retention, no aluminum rabbit emitted more than 30% CRs. Considered with the results of previous work, these data suggest that aluminum-induced neurofibrillary degeneration disrupts retention of the CR by affecting central associative processes.

Aluminum-induced neurofibrillary degeneration affects a subset of neurons in rabbit cerebral cortex, basal forebrain and upper brainstem

Neurofibrillary tangles in Alzheimer's disease show a predilection for cortical pyramidal and subcortical projection neurons. The antigenic composition, neuronal specificity and distribution of aluminum-induced neurofibrillary degeneration were examined in regions of rabbit brain analogous to those that develop neurofibrillary tangles in Alzheimer's disease. Neurofibrillary degeneration was induced by intraventricular instillation of aluminum chloride. In aluminum-treated rabbits, intensely immunoreactive filamentous aggregates were seen in affected neuronal perikarya after staining with an antiphosphorylated neurofilament antibody (SMI 31), while in controls immunoreactivity was confined to axon-like elements. Monoclonal antibodies against Microtubule-associated protein 2 and tau, which stain human neurofibrillary tangles, did not stain aluminum-induced neurofibrillary degeneration. Pyramidal neurons exhibiting neurofibrillary degeneration formed a discrete linear pattern in layers III and V of cortex. Cortical somatostatin and nicotinamide adenine dinucleotide phosphate diaphorase-reactive neurons identified in double-stained sections were unaffected. Large perikarya in the vicinity of the globus pallidus. some of which contained acetylcholinesterase, were frequently SMI 31-immunoreactive. Among the cell groups affected in the upper brainstem were the nucleus raphe dorsalis and locus coeruleus. These findings show that aluminum-induced neurofibrillary degeneration differs antigenically from neurofibrillary tangles in Alzheimer's disease. Nevertheless, many neuronal subsets that are particularly susceptible to Alzheimer's disease, including cortical pyramidal neurons, basal forebrain cholinergic neurons and upper brainstem catecholaminergic neurons, are also affected by aluminum-induced neurofibrillary degeneration.

Neurochemical characteristics of aluminum-induced neurofibrillary degeneration in rabbits

Aluminum-induced neurofibrillary degeneration in rabbits is known to affect particular populations of neurons. The neurotransmitter alterations which accompany aluminum neurofibrillary degeneration were examined in order to assess how closely they mimic those of Alzheimer's disease. There was a significant reduction in choline acetyltransferase activity in entorhinal cortex and hippocompus as well as significant reductions in cortical concentrations of serotonin and norepinephrine in the aluminum-treated rabbits. Significant reductions in glutamate, aspartate and taurine were found in frontoparietal and posterior parietal cortex. Concentrations of GABA were unchanged in cerebral cortex. Both substance P and cholecystokinin immunoreactivity were significantly reduced in entorhinal cortex but there were no significant changes in somatostatin, neuropeptide Y and vasoactive intestinal polypeptide. The five neuropeptides were unaffected in striatum, thalamus, cerebellum and brainstem. Neurochemical changes were found in the regions with the most neurofibrillary degeneration while regions with little or no neurofibrillary degeneration were unaffected. The reductions in choline acetyltransferase activity, serotinin and noradrenaline suggest that some neuronal populations preferentially affected in Alzheimer's disease are also affected by aluminum-induced neurofibrillary degeneration; however, the cortical somatostatin deficit which is a feature of Alzheimer's disease is not replicated in the aluminum model.

Age-related disruption of classical conditioning: A model systems approach to memory disorders

The model systems approach to the neurobiology of memory involves studying a well characterized learned response in a relatively simple and well controlled preparation. The best characterized mammalian model system is classical conditioning of the rabbit's eyeblink response. Using this preparation, significant progress has been made toward understanding the neurobiological systems and mechanisms involved in elaboration of the conditioned response. Using a well characterized model system such as classical eyeblink conditioning, it should be possible to both characterize the changes in learning and memory that accompany aging and to investigate their neural substrates. Our strategy for using the conditioned eyeblink preparation for studying age-related memory deficits is four-fold and includes investigating conditioning deficits in: (1) humans across the life span, (2) rabbits across the life span, (3) Alzheimer's disease patients, and (4) rabbits with aluminum-induced neurofibrillary degeneration. In this paper, we present exemplary data from each of these lines of research. If similar deficits occur in each of these groups, it may be possible to begin to form hypotheses about the neurobiology of age-related memory disorders.

Aluminum-induced neurofibrillary degeneration disrupts acquisition of the rabbit's classically conditioned nictitating membrane response.

Rabbits received intraventricular injections of aluminum chloride, hydrochloric acid, or served as unoperated controls. On the 6th day postsurgery, they underwent 4 days (100 trials per day) of classical conditioning of the nictitating membrane response (NMR) to a tone conditioned stimulus and an air-puff unconditioned stimulus. Unoperated and hydrochloric acid control animals readily acquired the conditioned response. Aluminum intoxicated rabbits, in contrast, did not acquire the conditioned response over the 4 days of testing. This disruption of conditioning in aluminum-treated rabbits could not be attributed to deficits in sensory or motor processes or to illness. Neuropathological analysis revealed widespread neurofibrillary tangle formation in aluminum-treated animals. Furthermore, the degree of neurofibrillary degeneration was significantly negatively correlated with the degree of conditioning. The results are considered in the context of using the rabbit NMR preparation as a model system for studying age-related conditioning disorders.

Aluminum-induced neurofibrillary degeneration disrupts acquisition of the rabbit's classically conditioned nictitating membrane response.

Aluminum-induced neurofibrillary degeneration disrupts acquisition of the rabbit's classically conditioned nictitating membrane response.

Origin and resolution of the aluminum controversy concerning Alzheimer’s neurofibrillary degeneration

Elevated concentrations of aluminum are found in regions of neurofibrillary change in brains with senile or presenile dementia of Alzheimer's type. The concentrations of aluminum found in the human disease are comparable to those found in experimental animals with aluminum-induced neurofibrillary degeneration (NFD). Although there are a number of reports confirming these observations, two laboratories have been unable to detect elevated levels in Alzheimer's disease. We conducted an interlaboratory study to resolve this discrepancy and traced the discrepancy to difficulties in analytical procedures. We concluded that failure to detect elevated aluminum levels associated with NFD is the result of (a) lack of strict adherence to the criteria for sample selection; (b) selection of too large a sample for analysis; and (c) use of analytical methodology that has potential matrix interference for the measured signal.

Cholinergic function in lumbar aluminum myelopathy.

To determine whether perikaryal neurofilamentous accumulation in cholinergic neurons is associated with a deficit in cholinergic function, we developed a new model of aluminum-induced neurofibrillary degeneration, referred to as focal lumbar aluminum myelopathy. The model is produced by direct intramedullary microinjection of AlCl3, which results in a characteristic neurological syndrome. Four weeks after injections, affected rabbits show extensive neurofilamentous lesions of both large and small neurons in the lumbar spinal cord, including a majority of anterior horn cells. These animals are capable of long-term survival. Posterior tibial nerve morphometry in these rabbits revealed no significant loss of myelinated fibers. Choline acetyltransferase (ChAT) activity in the sciatic nerve was decreased 39%, from 45.70 +/- 2.36 nmol ACh/hour/3-mm segment in acid-injected controls to 17.72 +/- 1.94 in aluminum-intoxicated rabbits. The rate of accumulation of ChAT activity proximal to a sciatic nerve ligature was significantly greater in the aluminum-treated rabbits, although the total amount of ChAT activity accumulating in a 24-hour period did not differ from controls. We conclude that aluminum-induced accumulation of neurofilaments in cholinergic perikarya is associated with a sharp decrease of ChAT activity in the axons of those cells and possibly with a compensatory increase in the rate of delivery of the enzyme.

Aluminum neurotoxicity in the absence of neurofibrillary degeneration in CA1 hippocampal pyramidal neurons in vitro

Neuronal dysfunction in experimental aluminum encephalopathy has been attributed to aluminum-induced neurofibrillary degeneration and the resultant neuronal loss. We observed a marked decline in neuronal function in the in vitro hippocampal slice taken from animals at various stages of the experimental encephalopathy. Extracellular evoked-potential analysis of the CA1 subfield revealed marked uncoupling of orthodromic spike generation and a decreased ability to demonstrate long-term potentiation. These effects were progressive and occurred in the absence of neurofibrillary degeneration.

Central cholinergic activity in aluminum-induced neurofibrillary degeneration.

Choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities were measured in spinal cord homogenates from rabbits with aluminum-induced neurofibrillary degeneration and a group of saline-treated, age-matched controls. All aluminum-treated animals showed neurofibrillary changes in the spinal cord, but CAT and AChE activities were not significantly different from levels in control animals. These results are at variance with the greatly reduced activity of these enzymes observed in Alzheimer disease and senile dementia of the Alzheimer type.

Observations on axoplasmic transport in rabbits with aluminum-induced neurofibrillary tangles

We have studied axoplasmic transport in rabbits as it is affected by aluminum-induced neurofibrillary degeneration. The analyses were performed 8–15 days after AlCl 3 administration except for one animal in which 30 days elapsed. Morphological changes were examined parallel to transport measurement. The anterograde fast axoplasmic component in the appropriate nerve was measured using [ 3H]leucine injected in the anterior horn of the L-7 level of the spinal cord and/or spinal ganglion at the same level. In both aluminum-treated and control animals, the rate of axoplasmic transport was similar at about 440 mm/day, and there was no correlation between this rate and the intensity of morphologic alteration. The effect of aluminum-induced neurofibrillary degeneration on retrograde axon transport was studied using Evans blue-albumin injected into the tongue. In all the controls and in one-half of the aluminum-treated rabbits, there was an accumulation of fluorescent granules in the perikarya of the XII cranial nucleus. In the rest of the experimental animals, fluorescent granules did not appear in the relevant perikarya.