Alzheimer’s disease (AD) steals memories and disrupts lives of 5.4 million Americans (according to Alzheimer’s Foundation statistics) and 26.6 million people worldwide. Moreover AD is predicted to affect 1 in 85 people globally by 2050! AD still cannot be cured and is degenerative, so the sufferer relies on others for assistance, placing a great burden on the caregiver, who are mostly spouses or close relatives.

Now a new study conducted by a group Harvard, Boston University, The University of Alberta, The University of Arizona, and The Chopra Foundation ascribe AD memory loss to disruption of microtubules by zinc imbalance (March 23 issue of the journal PLoS One).

AD brains have two types of lesions: beta-amyloid plaques outside neurons, and neurofibrillary tangles within them. The known AD genes implicate plaques, but AD symptoms correlate more closely with tangles, comprised of “tau” protein, that are normally adhered to microtubules. So AD might be the result of the building up of beta-amyloid proteins, which convert into plaques within the brain. Excess beta-amyloid plaques induce tangles, disrupt microtubules (MTs), and cause memory loss, even with normal synaptic function. But how does it work?

The new twist is that Beta-amyloid plaques outside neurons themselves aren’t destructive directly, but lead to lower zinc levels within neurons. Zinc stabilizes many protein complexes, including MTs, polymers of tubulin. MTs regulate synapses, and play recently-revealed key roles in memory encoding in neurons.

In the present study, Craddock et al: 1) identified specific zinc binding sites to tubulin promoting side-to-side tubulin interactions which are crucial to MT polymer structure; 2) used kinetic analysis to show how extra-neuronal zinc sequestration reduces intra-neuronal zinc available to tubulin, leading to MT destabilization and tangles; and, 3) presented metallomic imaging mass spectrometry (MIMS) of AD model mice, revealing abnormal zinc distribution in critical brain regions (see featured image).

This view of AD can lead to new therapies based on stabilizing MTs. This can be achieved by normalizing intra-neuronal zinc levels, using zinc ionophore drugs such as PBT2, or promoting MT self-assembly and stability by other drugs and transcranial therapies, e.g. ultrasound at MT resonant frequencies in megahertz.

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Citation and further reading:

Craddock TJA, Tuszynski JA, Chopra D, Casey N, Goldstein LE, Hameroff SR, Tanzi RE (2012) The Zinc Dyshomeostasis Hypothesis of Alzheimer’s Disease. PLoS ONE 7(3): e33552. doi:10.1371/journal.pone.0033552

Brookmeyer R, Johnson E, Ziegler-Graham K, MH Arrighi. Forecasting the global burden of Alzheimer’s disease.

Prana Biotechnology

The regions of the brain such as the hippocampus and the frontal cortex are densely populated with insulin receptors.  As well they are found in synapses in which insulin signaling participates in synaptic remodeling and synaptogenesis (1,2). In parallel insulin regulates the utilization of glucose in the hippocampus and other regions of the brain to promote optimal memory in normal metabolism (3).  In AD, it has been shown that reduced levels of insulin and insulin activity exist (4,5).  Interestingly insulin has a tight relationship to amyloid beta, a toxic peptide responsible for the onset of the disease.  Insulin can regulate the levels of amyloid beta to deliver protection from the degenerative nature of the peptide on neurons (6-8).

A pilot clinical trial published in the archives of neurology titled,  Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment, has shown insulin’ ability to be a protective new therapy in the fight against AD.  The trial hosted 104 participants, of which 30 participated in the use of a placebo, while insulin at 20IU and 40IU were delivered to 36 and 38 participants respectively.  The insulin was administered through a nasal drug delivery device for a total of 4 months. Surprisingly the 20IU and 40IU group experienced improved memory recall and preserved general cognition.

It was very important to identify a method of administration of insulin properly and direct to the brain without disrupting blood sugar levels.  When taken as a nasal spray it reaches the brain in just a few minutes with no apparent adverse affects on the body. Although a very promising study, it is still a preliminary study, more research will have to be carried out to ensure the safety and effectiveness of insulin as a therapy for longterm use against AD.

1. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708-719. PUBMED
2. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 2009;1792(5):482-496. PUBMED
3. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93(4):546-553. PUBMED
4. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50(1):164-168. FREE FULL TEXT
5. Steen E, Terry BM, Rivera EJ; et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. PUBMED
6. De Felice FG, Vieira MN, Bomfim TR; et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106(6):1971-1976. FREE FULL TEXT
7. Gasparini L, Gouras GK, Wang R; et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21(8):2561-2570. FREE FULL TEXT
8. Lee CC, Kuo YM, Huang CC, Hsu KS. Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol Aging. 2009;30(3):377-387. PUBMED

The response I got was less than enthusiastic. ‘But what’s the point of studying butterflies? Who would fund that?’ These questions are in reasonable complaints on the mind of many, non-scientists and scientists alike. A recent interview with the astronomer Neil deGrasse Tyson touches on the question of whether the exclusive purpose of science is some grand goal of bettering humanity. Certainly, a good deal of progress comes from funding smart people to do new and exceptional science with the hope that interesting findings produced will satisfy immediate objectives as well as serendipitous future outcomes.

I was happy to see the next day this article published in Nature nanotechnology, where silk moth antennae inspired technology that can improve diagnostics for critical diseases such as Alzheimer’s. Often, diagnostics that work on the molecular level work by being able to detect and/or distinguish the presence of certain molecules. For instance, an Alzheimer’s test might work by detecting the beta-amyloid plaques that are thought to be involved in the disease.

When nanopores are used, detection typically involves monitoring some change in the nanopore as a molecule passes through; there may be a change in voltage at the nanopore, or perhaps there is simply size exclusion (e.g.  molecule A can pass through the nanopore, but molecule B cannot). The design of the moth nanopores makes them resistant to clogging, a problem which has hampered previous artificial nanopore designs. The article’s authors speculate that their finding could in fact be used to develop a new Alzheimer’s diagnostic.

Perhaps a day spent observing butterflies is time well spent, rather than idle daydreaming.

Northwestern Medicine researchers have made a major discovery that can aid in understanding and treating Alzheimer’s. These researchers have taken human embryonic stem cells and transformed them into basal forebrain cholinergic neurons, those that die in early Alzheimer’s. The technology to grow these neurons in a laboratory will enable drug testing for treatment and also testing to study why these neurons die.

Researchers have demonstrated that these newly formed neurons work just like the originals. They were transplanted into the hippocampus of mice and were shown to function normally. The neurons produced axons to the hippocampus and pumped out acetylcholine, a chemical needed to retrieve memories.

These cells can be grown indefinitely in the lab, allowing for heavy amounts of research into these cells, something that’s never been done before. Perhaps now, with these new cells, we can be one step closer to understanding and treating this disease.

Cyrus Raji et.al. from the University of Pittsburgh have shown that loss in brain volume (a symptom of old age)  is decreased in those who are more physically active. A cohort of 299 adults (mean age of 78 years) were analyzed over the course of 13 years. After correcting for various factors, the Pittsburgh group concluded that walking around 72 blocks on average over 2 weeks, about 5 miles per week was enough to spare loss of brain volume.

Waking at a medium pace on a treadmill (2-3 miles per hour) can let you cover this distance in a half-hour. Even better, the study concluded that walking more than this distance did not help spare any more brain volume.

The study’s authors hope that this brain saving exercise regimen could help slow the progress of Alzheimer’s which is characterized by loss in brain volume, amongst other symptoms.  With the limited number of treatments now available for Alzheimer’s, any treatment, especially one as simple as a walk in the park is a valuable addition to preventing this disabling condition.

These findings were presented at the 2010 meeting of the Radiological Society of North America.

The point in mentioning these semantics is that the public is generally (kept?) unaware of how complicated the research process is, and how scientists who venture into discovering the unknown have to pick and choose their battles, making choices about how much or how many details they will pursue and at what cost.

It has been suspected for some time now that in Alzheimer’s the abnormal build up of plaques (formed by proteins called β-Amyloids) cause toxicity to neurons and damage the functioning of the brain. This finding was already a major step in fighting a devastating disease which is still poorly understood and which, not for lack of effort, has no satisfactory clinical intervention beyond attempts at early identification, some mildly successful drugs which may delay its onset, and general palliative care.

Recently, an investigation published here in the Journal of Biological Chemistry neatly illustrates how refined sleuthing can refine the instruments of inquiry available in the fight against Alzheimer’s and other debilitating diseases. The β -amyloid protein (APP) which has been the subject of previous study actually comes in three forms (APP₆₉₅, APP₇₅₁, and APP₇₇₀) which differ in the amino acid length of the protein. The work by Nikolai Belyaev et.al. demined that it this dangerous plaque is formed mainly by the APP₆₉₅ form which is found in higher concentration in brain and nerve cells. Identification of this particular APP isoform also explains the presence of another protein (AICD) which forms when the APP₆₉₅ isoform is broken down leading to activation of genes that further damage cells.

So why weren’t researchers focusing on this isoform before, instead choosing to study all three forms of APP (as if they were a single entity)? It’s a valid question. Was this negligence on anyone’s part? Mostly likely the answer is no. This new finding is simply the unfolding of the scientific process such as it is. For those who did the original work on looking at β -amyloid proteins, or any other proteins, there are only a limited number of questions that can be asked within a given time, given budget, or a given amount of accessible knowledge. Although the pace of research is in Alzheimer’s accelerating, the picture is never complete; pointed investigations like this one will continue to find gaps, and sharpen the focus as progress is made toward a cure.

According to research published in the Journal, Cerebral Cortex, by Stephanie McHughen  et.al., a key SNP in BDNF (valine 66 mutated to methionine) impacts learning and memory functions, cognitive tools which happen to be crucial for operating an automobile.

During one of the described experiments, subjects were seated at a computer, with attached steering wheel as they had to keep the virtual car on a black line in the center of the screen. Subjects got to learn the driving circuit by following the car on 15, 60 second trials.  While both groups of subjects (those who had the “normal” valine  allele, and those with the val⁶⁶met SNP) started at similar levels of ability, and showed short term learning. During the trials however, val⁶⁶met subjects showed less learning, and made more mistakes while learning. By day 5 of training, those with the val⁶⁶met allele showed less ability to retain the skills they had learned. The study also showed some differences in the activation of regions of the brain responsible for motor function and learning, such as the motor cortex.

Having this SNP is not all bad, as the val⁶⁶met SNP appears to be advantageous in disease settings, such as Alzheimer’s, Parkinson’s or multiple sclerosis, as it is thought that this SNP can increase the stability of certain brain functions, even though they may reduce plasticity in some learning tasks. In other words, this polymorphism may be the middle ground between flexibility and durability in brain functions.

I actually didn’t pass my road tests the first few times, and since my genotype happens to be heterozygous for this SNP I now have an excuse! My cello playing was never yo-yo ma, and but my teacher always commented that I had such a better time with difficult passages than simple ones. I wonder how this affects fine motor skills?

Jason – rs6265 (A/G)