Alzheimer’s and Kidney Disease: Common Molecular Culprit?

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The suspected molecular villain in Alzheimer’s disease (AD)—the amyloid precursor protein (APP)—may also play a role in kidney function, new research finds.

While the findings do not suggest that APP “causes” kidney disease, they reveal that this protein may play important, although poorly understood, roles in renal function. Continued research on APP may help unravel kidney disease’s complex mechanisms and prompt researchers developing drugs targeted for the treatment of AD to also examine the compounds’ effects on patients’ kidneys.

Thus far, APP’s complexity has defied numerous attempts by scientists to define how it might cause AD. In studies of brain tissue from AD patients and in animal models of the disease, APP has been implicated as a regulator of synapse formation and neural plasticity. Its expression is upregulated during differentiation and neuronal cell injury.

“We’ve known about APP since the late 1980s, but we’ve not yet determined APP’s role in the brain, much less other body organs and tissues,” said Lorenzo Refolo, PhD, a neuroscientist specializing in APP’s molecular and cell biology at the National Institute on Aging.

That said, APP is highly expressed throughout the kidney, said Daniel Biemesderfer, PhD, of Yale University School of Medicine. Biemesderfer’s lab has found that mice whose APP amyloid precursor–like protein-2 (APLP) genes were inactivated had a reduced glomerular filtration rate, lower urine osmolarity, and poorly developed renin granules in the juxtaglomerular cells.

“The distinct renal phenotype of the APP-/- mice suggests an important but not understood role in renal physiology,” Biemesderfer said.

Thomas Willnow, PhD, of the Max-Delbrueck-Center for Molecular Medicine in Berlin, traced the APP kidney connection to a unique protein— SorLA (sorting protein-related receptor)—that is expressed in both neurons and renal cells and that regulates APP processing. Polymorphisms in the gene that encodes this receptor have been associated with late-onset AD. Willnow spoke during the 2009 ASN Renal Week symposium, “Kidney-Brain: Emerging Parallels in Cell Biology.”

The kidney is not the only nonneural organ in which APP activity has been recently discovered. In papers published in 2008 and 2009, University of Vermont College of Medicine scientists reported that APP is highly expressed in adipose tissue and is upregulated in obesity. The researchers correlated APP expression levels with insulin resistance and adipocyte cytokine expression levels, suggesting a possible mechanism linking midlife obesity with the later development of AD.

The link between the kidney and brain is exemplified by the occurrence of drug toxicities that include the kidney and ear (in aminoglycosides, for example) and genetic syndromes that affect both organs, such as Bartter syndrome, with sensorineural deafness. Bartter syndrome is a genetic disorder accompanied by hypokalaemic metabolic alkalosis. The most severe phenotype for Bartter syndrome is characterized by life-threatening neonatal volume depletion and chronic renal failure developing during infancy.

The brain-kidney link is also illustrated by the name given to a scaffolding protein identified in 2002 by scientists at the University of Münster in Germany. Expression of mRNA for the protein, named KIBRA (kidney and brain), was detected in both organs, according to the scientists’ paper, “Characterization of KIBRA, a novel WW domain-containing protein,” published in Biochemical and Biophysical Research Communications.

These and other studies have revealed that KIBRA is expressed in the glomeruli, tubules, and collecting duct, as well as in the brain’s memory-related regions including the hippocampus and cortex.

The University of Munster’s Hermann Pavenstädt, PhD, reported in a 2008 paper in Journal of the American Society of Nephrology that directional cell migration is disturbed when KIBRA expression is reduced. In addition, Pavenstädt and his colleagues found that KIBRA directly interacted with synaptopodin, a podocyte protein that plays a role as cytoskeletal organizer and that is also associated with synaptic plasticity in neurons.

In the brain, KIBRA represents a component of the postsynaptic density, the researchers said. “Thus, our data support the hypothesis that the motility of podocyte foot processes and the flexibility of synaptic contacts of neurons could be regulated by an analogous set of molecules, including proteins such as KIBRA, synaptopodin, dendrin, actin, and actinin.”

Because foot processes and dendrites are long F-actin–rich cellular extensions, KIBRA may play a role in the continuous regeneration and plasticity of both cell types.

The kidney-brain connection is a “real hot spot” in research, said Sebastian Bachmann, PhD, professor and chairman of anatomy and cell biology at the Humboldt University in Berlin.

“Leading papers from world class scientific groups are currently focusing on this issue and find substantial material that proves it is worthwhile to concentrate on common mechanisms in kidney and brain,” Bachmann said. “This is well exemplified with APP and SorLA in both organs.”

Since its discovery, most research on APP has targeted the brain and has led to the “amyloid hypothesis,” which proposes that flaws in the production, accumulation, or disposal of β -amyloid, an APP microscopic protein fragment, somehow trigger Alzheimer’s, perhaps by clogging points of cell-to-cell communication, thus activating immune cells that trigger inflammation and devour disabled cells.

Although APP’s normal function has not yet been defined, scientists have discovered that in its complete form, APP extends from the inside to the outside of brain cells by passing through a fatty membrane around the cell. When APP is activated to do its normal job, it is cut by other proteins into smaller sections that stay inside and outside cells. One of the sections, β-amyloid, is chemically “stickier” than other APP fragments and accumulates by stages into microscopic amyloid plaques that are considered a hallmark of brains affected by Alzheimer’s.

According to the Alzheimer’s Association, several experimental drugs targeting β -amyloid have reached human clinical trials, but more time and studies are required before these compounds’ effects on Alzheimer’s symptoms or on brain cells can be clearly determined.

The results of Willnow’s studies at the Max-Delbrueck-Center for Molecular Medicine indicate that low levels of SorLA are a primary cause of accelerated production of amyloid β-peptide, the principal component of senile plaques, and of senile plaque formation. Willnow’s lab has shown that SorLA regulates intracellullar transport and processing of APP. Indeed, his lab also has found that high levels of SorLA expression reduce—and low levels of SorLA promote—senile plaque formation. Thus, altered SorLA activity may be an important risk factor for AD, according to Willnow.

Willnow hypothesizes that in the kidney, SorLA controls trafficking and activity of SPAK, an enzyme that regulates the cellular stress response and is part of a signaling pathway that regulates salt transport and blood pressure.

In kidney cells, SorLA also may influence the intracellular trafficking of shuttling compartments that contain the protein aquaporin2 (AQP2), regarded as “the plumbing system for cells.” AQP2s are located in the apical cell membranes of the kidney’s collecting duct and in intracellular vesicles located throughout the cell.

SorLA is mainly localized in the cell’s Golgi apparatus, where it interacts with target proteins such as APP. Willnow has demonstrated that the Golgi’s premature release of APP due to low SorLA activity subjects APP to accelerated proteoltyic cleavage into amyloid peptides. These results may explain how AD pathology is affected by the activity of the sorting receptor SorLA in the brain.

Willnow’s lab has not yet investigated APP in the kidney. “Our main interest is the functional characterization of SorLA in the kidney,” he said. “Of course, we will also explore whether the activity of the receptor in the kidney may include control of APP processing in renal cell types and what the physiological relevance of APP and its processing products may have in the kidney.”

Findings from the Biemesderfer lab indicate the presence of what appears to be previously unknown signaling pathways in the kidney that involve APP and APLP.

Biemesderfer and his colleagues became interested in APP after discovering that the proximal tubule scavenger receptor megalin is subjected to regulated intramembrane proteolysis (RIP). Suspecting that RIP’s relationship with megalin may represent part of a signaling pathway linking events at the brush border with regulation of target gene expression, the lab conducted research that led to the identification of ADAM10 as a proximal tubule protease. The ADAM10 findings suggested that the proximal tubule has other receptors that are subjected to RIP.

“From some old literature we noticed that there are large amounts of APP and APLP2 mRNA in kidney,” said Biemesderfer. Based on this information, his lab initiated the studies that found high levels of APP and APLP2 in adult mouse kidney and in several proximal tubule cell lines. The lab then identified where renal APP is expressed along the nephron. They localized APP at the cellular and subcellular levels in mouse kidney and described the renal phenotype of APP-/- mice, whose APP and APLP2 genes have been inactivated.

“Our data suggest that these proteins are involved in signaling pathways in proximal tubule that may regulate gene expression,” Biemesderfer said.

In other work, Rong Cong, PhD, and colleagues in Biemesderfer’s lab reported that the protease ADAM10 and APLP2 are expressed in cultured proximal tubule cells. They also reported that ADAM10 activity has a pronounced effect on expression of specific proteins of the renal brush border.

Biemesderfer’s lab continues to investigate APP in the kidney. “Our goal is to understand how APP and APLP2 function in kidney and especially in the proximal tubule,” he said. “Based on gene knockout studies in brain, it is thought that APP and APLP2 serve redundant functions. Therefore, our next study will use mouse genetics to knock out both genes in proximal tubule. We predict a phenotype that will give us important clues as to the function of these proteins in this part of the nephron.”