Response to: Walton JR (2012) J Alzheimers Dis 29, 255-273

1 April 2012

I read about the effects of aluminum on brain with features of aging and calcium signaling with interest [1]. The effects of aluminum on the brain in the pathogenesis of Alzheimer’s disease (AD) may play out at the blood brain barrier. Aluminum enhances the permeability of the blood-brain barrier to lipophilic substances [2] and the central part of the amyloid-β peptide (Aβ), the alpha helical antigenic folding domain of the Aβ folding peptide loop is lipophilic [3]. Studies have indicated that some of the Aβ present in AD patients was from peripheral blood, and endogenous bloodborne Aβ has been found to cross the blood-brain barrier by a non-saturable mechanism [4].

Aβ and hyperphosphorylated tau deposits have been found in the pancreas of patients with type 2 diabetes [5]. Aβ may escape into the circulation from the pancreas, especially in patients with type 2 diabetes, and cross the blood-brain barrier, especially if it has been primed by aluminum exposure, which increases its permeability to lipophilic substances such as Aβ. The increased brain exposure to Aβ may in turn cause increased likelihood of developing AD in susceptible individuals.

Although the effect of aluminum on development of AD remains controversial, certainly increased amounts of Aβ are thought to increase the likelihood of developing AD. If the blood-brain barrier is exposed to aluminum, it may in turn cause increased amounts of Aβ to accumulate in the brain with subsequent neurotoxicity and development of AD. Aluminum is not necessarily toxic in its own right, but may cause increased exposure of the brain to the neurotoxin, Aβ, one of the main components of AD, by permitting it to pass through the blood-brain barrier at an increased rate.

Steven R. Brenner, MD
Affiliated with St. Louis University
Department of Neurology and Psychiatry
St. Louis, MO, USA
Tel: 314-977-6082

[1] Walton JR (2012) Aluminum disruption of calcium homeostasis and signal transduction resembles change that occurs in aging and Alzheimer’s disease. J Alzheimers Dis 29, 255-273.
[2] Banks, WA, Kastin AJ (1985) Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull 3, 287-292.
[3] DeMager PP, Penke B, Walter R, Harkany T, Hartignny W (2002) Pathological folding in Alzheimer’s disease and other conformational disorders. Curr Med Chem 19, 1763-1780.
[4] Maness, LM, Banks WA. Podlinsy MB, Selkow DJ, Kastin AJ (1994) Passage of human Amyloid B-protein 1-40 across the murine blood-brain barrier. Life Science 55, 1643-1650.
[5] Miklossy J, Qing H, Radenovic A, Kis A, Vileno B, Laszlo F, Miller L, Martins RN, Waeber G, Mooser V, Bosman F, Khalili K, Darbinian N, McGeer PL (2010) Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging 31, 1503-1515.


Aluminum is a Neurotoxin in its Own Right

I have read Dr Brenner's interesting hypothesis that aluminum may facilitate pancreas-derived amyloid-β (Aβ) transport across the blood-brain barrier. This deserves to be examined and tested by epidemiological studies to determine the extent to which the pancreas may contribute to the brain’s Aβ burden in addition to that produced in situ by astrocytes and neurons [1]. I note that Dr Brenner has yet to accept that aluminum is a neurotoxin. There are occasional reports in the literature that could give this impression. However, the apparent absence of aluminum toxicity in aluminum-exposed cells or animals usually indicates that the duration of exposure has been too brief. Alternatively, the aluminum dose could have been too high. An excess of aluminum causes aggregation of polynuclear aluminum species and formation of precipitates that severely reduce the actual amount of aluminum delivered to the cells. Also, the criterion for assessing neurotoxicity needs to be appropriate. Some toxins such as 1-methyl-4-phenylpyridinium ion (MPP) act by killing cells which results in leakage of lactic acid dehydrogenase into the cell medium [2]. Aluminum is different.

Aluminum salts exert their neurotoxicity by crippling cell function instead of killing cells outright. Aluminum preferentially deposits in pyramidal cells of brain regions that are also vulnerable to damage in AD. Aluminum neurotoxicity in individuals with normal kidney function depends on slow accumulation over time in cortical and hippocampal cells where aluminum causes damage by (i) competing with essential metals in key regulatory reactions, (ii) producing oxidative stress, and (iii) disrupting cellular metabolism in general. Such disruption can interfere with neuronal calcium signaling and neurotransmission as described in my recent review article [3].

High stage aluminum accumulation in neurons blocks microtubule formation, resulting in dendritic dieback and loss of synapse density [4]. Aluminum participates in the formation and growth of neurofibrillary tangles in AD brains [5]. Also, an aluminum-inducible animal model for AD develops cognitive deterioration in old age, with AD-relevant neuropathology [4], after chronically ingesting aluminum in equivalent amounts to those ingested by Americans from processed food, alum-treated drinking water, and other sources of aluminum additives [6].

Aluminum neurotoxicity has been demonstrated at all levels, from sub-nanomolar levels of produced in a carefully defined system [7] to human populations where aluminum neurotoxicity has caused and/or contributed to various types of dementia [8-11]. For example, 19/20 dialysis patients (aged 32-64 years old) died after developing dialysis dementia in the period 3 months to 4 years after Chicago altered its method of water purification in June 1972. This change involved higher aluminum levels (peaking between 300 and 400 μg/L) in the drinking water [8].

Dr. Brenner refers to Aβ neurotoxicity. A substantial body of evidence attests to Aβ being a by-product of aluminum neurotoxicity (reviewed in [12]). On balance, there seems to be far more evidence for in vivo aluminum neurotoxicity than for in vivo Aβ neurotoxicity.

J.R. Walton, PhD
UNSW Faculty of Medicine, University of New South Wales, St George Hospital Campus, Sydney, NSW, Australia

[1] Busciglio J, Gabuzda DH, Matsudaira P, Yankner BA (1993) Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Nat Acad Sci U S A 90, 2092-2096.
[2] Shimma N, Akiyama N, Umezawa M, Okuma Y, Nomura Y, Saito T, Horie S, Murayama T (2003) Possible role of interleukin-6 in PC12 cell death induced by MPP+ and tetrahydroisoquinoline. J Pharmacol Sci 93, 471-477.
[3] Walton JR (2012) Aluminum disruption of calcium homeostasis and signal transduction resembles change that occurs in aging and Alzheimer's disease. J Alzheimers Dis 29, 255-273.
[4] Walton JR (2009) Brain lesions comprised of aluminum-rich cells that lack microtubules may be associated with the cognitive deficit of Alzheimer’s disease. Neurotoxicology 30, 1059-1069.
[5] Walton JR (2010) Evidence for participation of aluminum in neurofibrillary tangle formation and growth in Alzheimer's disease. J Alzheimers Dis 22, 65-72.
[6] Walton JR (2009) Functional impairment in aged rats chronically exposed to human range dietary aluminum equivalents. Neurotoxicology 30, 182-193.
[7] Miller JL, Hubbard CM, Litman BJ, Macdonald TL (1989) Inhibition of transducin activation and guanosine triphosphatase activity by aluminum ion. J Biol Chem 264, 243-250.
[8] Dunea G, Mahurkar SD, Mamdani B, Smith EC (1978) Role of aluminum in dialysis dementia. Ann Intern Med 88, 502-504.
[9] Alfrey AC, LeGendre GR, Kaehny WD (1976) The dialysis encephalopathy syndrome, possible aluminum intoxication. N Engl J Med 294, 184-188.
[10] Yasui M, Yase Y, Ota K, Garruto RM (1991) Aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii Peninsula of Japan. Neurotoxicology 12, 615-620.
[11] Kobayashi S. Hirota N, Saitio K (1987) Aluminum accumulation in tangle-bearing neurons of Alzheimer’s disease with Balint’s syndrome in a long-term aluminum refiner. Acta Neuropathol 74, 47-52.
[12] Walton JR (2012) Evidence that ingested aluminum additives contained in processed foods and alum-treated drinking water are a major risk factor for Alzheimer's disease. Curr Inorg Chem 2, 19-39.