As the baby boomer generation continues to age, the prevalence of neurological diseases, such as Alzheimer’s Disease (AD) and Dementia of the Alzheimer’s Type (DAT), will increase at a dramatic rate. Alzheimer’s Disease is a progressive neurological disorder characterized by severe memory loss, dementia, and cognitive and behavioral impairment (1). It is predicted that by 2050, the cost of health care for Alzheimer’s Disease alone will equal a total of $1 trillion as the number of patients being treated for AD triples. This cost would bankrupt the healthcare system, and in turn, bankrupt the U.S. economy (2). Based on these projections, the treatment of neurological diseases not only becomes a scientific issue, but also a political one, seeing as the U.S. defense budget is already $1 trillion. About two-thirds of the cost of treatment for AD will be covered by Medicare and Medicaid, demonstrating how most of the cost will become the responsibility of the taxpayers – the current millennials. George Vradenburg, Chairman, President, and Founding Board Member of UsAgainstAlzheimer’s organization, expressed his concern by stating, “Alzheimer’s will be the financial sink hole of the 21st century (2).” As the millennial generation approaches this thirty-year limit, there is a dire need to recognize the demand for neurological disease research focused on discovering biomarkers for proactive, early diagnosis of AD. According to Thomas Insel’s TED Talk, “Toward a New Understanding of Mental Health,” given in April of 2013, by the time affected individuals are diagnosed, a significant amount of degeneration and brain atrophy has already occurred. Insel, the director of the National Institute of Mental Health (NIMH), emphasized the lack of research funding and focus in the past two decades on the treatment of Alzheimer’s Disease. In 2011, while research and treatment for other diseases, such as cancer, cardiovascular disease, AIDS, and stroke have received well over $1 billion each, Alzheimer’s Disease treatment only received a little over $400 million (3). Without the proper funding, clinical research remains limited, underscoring the important role that government plays alongside scientists in drug advancement.

The main focus of clinical research is to trace the origins of diseases and disorders to their causes in order to prevent such illnesses from arising. Currently, such an approach is being taken by researchers and physicians desperately trying to find cures for Alzheimer’s Disease. Many of these approaches involve discovering biomarkers for protein levels that correlate with the degree of neuronal degeneration and brain atrophy that occurs as Alzheimer’s progresses. In September 2017, the FASEB Journal (Federation of American Societies for Experimental Biology) published a paper by Edward Goetzl, et.al., “Decreased Synaptic Proteins in Neuronal Exosomes of Frontotemporal Dementia (FTD) and Alzheimer’s Disease (4).” In this article, the authors attempted to measure neuronal derived exosomes

(NDEs) from the blood of patients with AD, FTD, and their gender- and age-matched controls. Neuronal derived exosomes are vesicles that contain neuro-specific cargo in the central nervous system (CNS). These vesicle-like vehicles in the CNS transport lipids, RNA, and synaptic proteins that function in vesicle fusion, calcium regulation, and release of neurotransmitters in the brain. Synaptic proteins function in the transmission of signals in the nervous system through regulation of neurotransmitter release, chemicals in the brain involved in movement, homeostasis, etc. Goeztl and team, understanding that both AD and FTD are progressive diseases that have no cure, attempted to identify six synaptic proteins in NDEs and measure their levels of abundance. During AD and FTD – which is characterized by frontal and temporal lobe atrophy and behavioral impairments – neurons die and connections between the brain and body are lost. Specifically, neuropathology of Alzheimer’s involves amyloid-beta plaques and neurofibrillary tangles, which in the late stages of AD spread to all four lobes of the brain, resulting in severe impairment of daily living.

Amyloid-beta plaques, more commonly known as senile plaques, contain improperly-folded protein surrounded by a composition of immune cells. The plaques aggregate in the extracellular fluid and the cerebrospinal fluid (CSF), which disrupt neurotransmitter transport and synaptic connections in the brain. Amyloid-beta plaques form due to over-activation of beta-secretase and gamma-secretase, enzymes that cleave the Amyloid Precursor Protein (APP). The function of APP is not yet known, but if both beta- and gamma-secretase cleave APP, an amyloid-beta peptide is released into the extracellular space. A specific peptide, Ab42, has a high tendency to bind other Ab42 peptides, forming a multimer of Ab peptides that signals an inflammatory response to send immune cells to the sight of aggregation. As a result, the amyloid-beta plaques become surrounded by inflammatory cells, forming senile plaques in the CSF. Additionally, imaging techniques have also shown prominent neurofibrillary tangles (NFTs) inside neurons, which are composed of fibrils that form from axonal building blocks. According to the Amyloid Cascade Hypothesis, amyloid-beta plaques interfere with the regulation of other enzymes, such as kinases, causing a separate protein, tau, to become heavily negatively charged. Tau protein is responsible for maintaining the structure of microtubules, and the accumulation of negative charge causes the tau proteins to disassociate from axonal building blocks, shattering the structural components of the neuron’s intracellular trafficking. These NFTs can then spread and accumulate with the amyloid-beta plaques in the CSF, inhibiting chemical signaling and initiating brain atrophy.

Goeztl and his research team attempted to find biomarkers of this neuronal decay in the form of lower levels of the proteins involved in chemical signaling and connections between neurons that should accompany neuron death in AD and FTD. As expected, the researchers found that the six synaptic proteins in the NDEs (synaptotagmin, synapsin-1, synaptophysin, synaptopodin, GAP43, and neurogranin) were decreased in individuals with AD compared to the matched controls. They also found that greater decreases in synaptic proteins correlated with more severe cognitive impairment and memory loss. These results indicate a direct correlation between senile plaque and hyper-phosphorylated tau toxicity and the loss of synapses that leads to dementia, and they point toward the future discovery of ways to prevent this decrease in synaptic protein levels. For example, possible therapies that are being investigated as a result of this paper are beta- and gamma-secretase inhibitors, acetylcholine-esterase inhibitors, immunotherapy targeting amyloid-beta plaques, and more.

While these methods appear promising, more government funding must be directed towards Alzheimer’s Disease research to see even a glimpse of hope for a cure as the next generation ages. AD affects 1 in 6 individuals of age 65 or older and 1 in 2 individuals of age 85 and older, and the hallmark amyloid-beta plaques and neurofibrillary tangles can begin to form as early as 10-15 years before diagnosis. Given these numbers, it is imperative that research to discover proactive treatment for AD receive appropriate funding and focus. Until this occurs, Alzheimer’s Disease remains a race against time.


REFERENCES

  1. Savonenko, Alena V., et al. “Alzheimer Disease.” Neurobiology of Brain Disorders, Chapter 21, no. Neurobiology of Brain Disorders, 2015, pp. 321–338.,doi:10.1016/b978-0-12-398270- 4.00021-5.
  2. Arledge, Elizabeth and Gerry Richman, directors. Alzheimer’s: Every Minute Counts. TBT National Productions, 2017.
  3. “NIH Categorical Spending -NIH Research Portfolio Online Reporting Tools 2011 (REPORT).” National Institutes of Health, U.S. Department of Health and Human Services, report.nih.gov/categorical_spending.aspx.
  4. Goetzl, E J, et al. “Cargo Proteins of Plasma Astrocyte-Derived Exosomes in Alzheimer’s Disease.” FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology., U.S. National Library of Medicine, Nov. 2016, www.ncbi.nlm.nih.gov/pubmed/27511944.

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