Cognitive deterioration and associated pathology induced by chronic low-level aluminum ingestion in a translational rat model provides an explanation of Alzheimer's disease, tests for susceptibility and avenues for treatment

Abstract

A translational aging rat model for chronic aluminum (Al) neurotoxicity mimics human Al exposure by ingesting Al, throughout middle age and old age, in equivalent amounts to those ingested by Americans from their food, water, and Al additives. Most rats that consumed Al in an amount equivalent to the high end of the human total dietary Al range developed severe cognitive deterioration in old age. High-stage Al accumulation occurred in the entorhinal cortical cells of origin for the perforant pathway and hippocampal CA1 cells, resulting in microtubule depletion and dendritic dieback. Analogous pathological change in humans leads to destruction of the perforant pathway and Alzheimer's disease dementia. The hippocampus is thereby isolated from neocortical input and output normally mediated by the entorhinal cortex. Additional evidence is presented that Al is involved in the formation of neurofibrillary tangles, amyloid plaques, granulovacuolar degeneration, and other pathological changes of Alzheimer's disease (AD). The shared characteristics indicate that AD is a human form of chronic Al neurotoxicity. This translational animal model provides fresh strategies for the prevention, diagnosis, and treatment of AD.

Figure 1

Some humans absorb more Al than others. Plasma ²⁶Al levels in humans who drank ²⁶Al with orange juice, and ²⁶Al with orange juice plus silica. Silica lowers the amount of Al absorbed. The different individuals exhibit a spread of plasma Al values from (A) to (E), the highest being approximately three-fold times greater than the lowest. Note that ranking of subjects' plasma values is almost in the same order on both occasions. Reproduced from [19] with permission from Elsevier.

Figure 2

Staging of aged rat (upper row) and aged human (lower row) hippocampal CA1 neurons stained for Al [30, 31] show progressive Al accumulation accompanied by cytopathological change. Stage 0: the entire cell appears Al-negative and has normal morphology; this stage is not observed in the aged human specimens. Stage I: magenta nucleolus, no other staining for aluminum. Stage II: magenta nucleolus in pink nucleoplasm with visible chromatin; the cytoplasm is blue. Stage III: magenta nucleolus in an elongated or irregularly shaped purple nucleus. The cytoplasm is blue. Many apical dendrites from this stage onwards have a serpentine appearance. Stage IV: the magenta staining appears in the elongated nucleus which now shows less structural detail; the shrunken cytoplasm is still blue. Stage V: purple to magenta staining appears throughout the nucleus and cytoplasm. Cell shape is distorted and the axon and dendrites are disrupted. Magnification bar (MB) = 15 μm, Reproduced from [31].

Figure 3

Entorhinal cortical cells with stage IV Al accumulation from rats with cognitive deterioration. (a) Low-magnification view of an island containing some cells with high-stage Al staining and others with normal morphology. (b) Island of stellate entorhinal cortical cells at high optical magnification. MB = 50 μm.

Figure 4

Al accumulation in a lesion of hippocampal CA1 cells in a rat with cognitive deterioration correlates with microtubule depletion. (a) The stage IV pyramidal cells in the center stain magenta for nuclear Al. Pyramidal cells with a normal appearance (arrows) are present along the margins of the lesion. (b) An adjacent section, immunostained for acetylated tubulin, demonstrates that cells within the lesion, corresponding to those with stage IV Al staining, are microtubule depleted. Other pyramidal cells at the margins of the lesion have a more normal appearance and clearly immunostain for microtubules (arrows). MB = 50 μM. Republished from [31].

Figure 5

Camera lucida drawings of Golgi-stained AD hippocampal pyramidal cells that illustrate the process of dendritic dieback (left to right). The deteriorated cell at far right resembles some of the Al-rich microtubule-depleted cells in the hippocampal lesion of Figure 4(b). Redrawn from [45] with permission from Elsevier.

Figure 6

Dendritic dieback in AD brain revealed by immunostaining for microtubules. (a) Glial cells in the stratum radiatum appear to clip dendrites into segments. Portions of glial cell cytoplasm insert between dendritic segments (arrows). (b) Segmented dendrites of the stratum radiatum from an AD case. The arrow points to segmentation that interrupts dendritic microtubules. MB = 2.5 μm. Republished from [31].

Figure 7

Schematic representation of the perforant pathway. The perforant pathway is similar for humans and rats apart from minor variations. (1) The cells of origin (CO) for the perforant pathway (PP) reside in layer II (shown as cell islands) and in the superficial part of layer III of the entorhinal cortex (EC). The cells of origin receive information from many cortical regions. (2) Axons of the cells of origin converge in the angular bundle (AB) from which the perforant pathway emerges. (3) Upon leaving the angular bundle the axons (4) diverge into fascicles known as the perforant pathway (PP) because they perforate the gray matter of the subicular cortex (SC) on their way to the hippocampal formation. (5) A contingent of fascicles enters the stratum lacunosum moleculare (SLM) of the CA1/subicular zone (CA1) and terminates on pyramidal cell dendrites. (6) More fascicles cross the hippocampal fissure (HF) (7) to enter the molecular layer (ML) of the dentate gyrus (DG) and terminate on distal dendrites of granule cells in the outer two-thirds of this molecular layer. Based on information contained in [63] with permission from John Wiley and Sons.

Figure 8

Hippocampal circuitry. Representative morphology of CA1 and CA3 pyramidal cells and a dentate granule cell (GC). The axon of the granule cell gives off collaterals in the hilus and a long branch (mf) extends into the CA3 field as a mossy fiber that contacts heavy thorns on the CA3 pyramidal cell. The axon of the CA3 pyramidal cell gives off a Shaffer collateral (SC) in the stratum oriens which ascends to the stratum lacunosum moleculare. The axon of the CA1 pyramidal cell bifurcates into long extensions within the white matter. Republished from [57] with permissions from Elsevier and the author.