A new paper from researchers at the Case Western Reserve University School of Medicine challenges the classic theory that the nerve tangles seen in the brains of Alzheimer's disease (AD) victims are the cause of the disease, but rather proposes that they are a protective response to the disease. Their paper appears in the April issue of the journal Trends in Molecular Medicine.
The tangles, called neurofibrillary tangles (NFTs) by scientists, are one of the major features seen in brains of people with AD. The major component of NFTs is a protein called tau which has undergone a biochemical reaction called phosphorylation, and it is widely assumed that NFTs are central to the progression of AD and nerve cell death. Yet these tangles also occur to some extent in all brains with age although typically there are a lot more in the brains of people with AD.
"However, the correlation between the presence of NFTs and incidence of disease does not necessarily dictate a causal relationship" said lead author, Hyoung-gon Lee, Ph.D., a research associate in the Department of Pathology at Case. "In fact, since NFTs are produced in response to a variety of disease conditions, there is the distinct possibility that tau phosphorylation has an alternate role in disease - one that proceeds rather than precedes it."
So, what evidence is there to support a non-pathogenic role for NFTs in AD?
First of all, according to the researchers, tau phosphorylation or fibril formation itself is unlikely to be the harbinger of neuronal death since NFT-bearing neurons appear to survive for decades. In fact, one study found that neurons containing NFTs can survive for as long as 20 years.
Senior author, Mark A. Smith, Ph.D., professor of pathology at Case, noted, "These findings are in accord with our own published findings showing that NFTs are not only a relatively late event in the chronology of the disease, occurring decades after oxidative stress, but might also represent a response aimed at reducing oxidative damage."
There is growing evidence that oxidative stress is a significant factor in the development of AD. Free radicals and reactive oxygen species oxidize tissues. Rusting metal is a process of oxidization, for example. In tissue, oxidization damages membranes and DNA, disrupting normal cell function and leading to nerve cell death.
"Since oxidative stress is decreased in neurons bearing NFTs," Smith added, "we suspect that the accumulation of tau proteins might actually be a protective, antioxidant response that serves as a mechanism for cells to defend themselves."
While such a "good" role for tau phosphorylation goes against the grain of current dogma, Lee noted, "A protective role of tau phosphorylation is further supported by the fact that embryonic neurons that survive after treatment with oxidants have increased tau phosphorylation relative to those that die. It is also apparent that NFT-like tau phosphorylation occurs during hibernation, a neuroprotective phenomenon."
"Therefore, Smith added "the regulation of tau phosphorylation in the adult mammalian brain appears to represent a naturally occurring process associated with neuroprotective mechanisms." In support of this, previous work by Smith's group found that cellular antioxidant induction and tau expression are opposing, suggesting that the reduced oxidative damage in neurons showing tau accumulation may be a direct consequence of an antioxidant function of phosphorylated tau.
This group's alternate view of protein aggregation in AD is not limited to NFTs. Lee, Smith and colleagues also believe that amyloid-beta, another aggregated protein found in AD, could play a key role in protecting neurons and, like NFTs, be an antioxidant.
And they are not alone. Recently, it was reported by another research group that the protein aggregates associated with Huntington's disease are associated with increased cell survival.
"After nearly a century of viewing pathology as pathogenic, our accumulating data called for a paradigm shift where pathology is protective," said Lee. "If proven correct, this will not only change current dogma but, more importantly, reveal key insights to accelerate the development of new therapeutic inroads."
In addition to Lee and Smith, co-authors represented the key contributions and insights of a decade-long team-effort by current (George Perry, Ph.D., Matthew R. Garrett, Paula Moreira, and Xiongwei Zhu, Ph.D.) and former members (Quan Liu, Ph.D., Atsushi Takeda, Ph.D., and Akihiko Nunomura, Ph.D.) of the Institute of Pathology at Case.