As many already know and have watched the movie “Still Alice”, based on the same name bestselling novel by Lisa Genova in 2007, is the story of a university professor in linguistics with an early onset Alzheimer’s disease. The movie brought more recognitions and many awards across the globe and finally the most prestigious of all, Golden Globe and Academy awards, for Julianne Moore who played the role of Alice Howland, the Columbian University professor.
While it is commendable that Hollywood addresses medical and mental suffering of people at large, but it also needs to consult with the medical profession for the validity of its portrays on the screen. Although anybody can catch any disease including Alzheimer’s but there are certain protective factors against almost any disease, as high education and intelligence is against development or clinical presentations of Alzheimer’s disease, so there would be a lower risk or late and slow clinical presentations of the disease in a highly educated university professor. This fact proven by many research over the past couple of decades has created the “cognitive reserve” theory and the possibility of non-pharmaceutical prevention and intervention of this devastating disease by maintaining our brains active as a safeguard to certain degree! Therefore it had been more prudent if Julianne Moore, whom I have a great adoration, would have said more about Alzheimer’s disease in her Oscar acceptance speech, instead of saying “ I have read an article that winning Oscar, leading to living 5 years longer!” that was totally inappropriate and unexpected. To finish off this introduction and leave Hollywood with their more informed film making and interpretations of real life problems and diseases, I need to emphasize the importance of high education and intelligence and keeping our brains active as the only probable preventive measures against this man knocking down disease at the present time.
Alzheimer’s disease (AD) which is the most common type of dementia and accounts for up to %70 of such cases, carries its label from the German psychiatrist, Alois Alzheimer who identified the first case of such condition in a 50 year old woman in 1901. Despite the first reported case by Dr. Alzheimer’s and the character in the movie “Still Alice” being young, the early onset AD is rare and the majority of cases are first diagnosed after age 65 and the risk of disease is higher with the older age, so that incidence rises from 3% in 60’s to about %25-40 in 80’s and about %70 in 90’s. In fact and as we will read further here, senescence and the old age is associated with some cognitive and memory loss due to the aging of the brain and its neurons like aging of the rest of the body and loss of its functions and youth.
Despite the common belief among the experts of AD being a genetic disease, the genetic heritability of this disease has such a wide range of %50-80 in twin and family studies that questions the totality of it as being hereditary. Moreover as discussed elsewhere in this website, genetics or mutations of genes are not causes of disorders but paths of transcriptions and transmissions. Therefore the common sense dictates to search for a cause(s) that lead(s) to such faulty mutations, then transcriptions and transmissions so fooling us to perceive genetics as cause(s) of diseases! In relation to AD, in fact as early as 1980’s, there has been report and scientific suspicion as viral insults being a cause of the disease. While in the past there was a disbelief about viral existence in our brains, Itzhak in 1994 reports of such finding in his lab, that herpes simplex type I virus (HSV1) DNA, the cause of common and recurrent oral herpes or “cold sores”, is present in many normal aged brains and AD brains, but absent in brains of younger people. The viral association with AD, specially HSV1 has been reported as early as 1980 by Middleton and colleagues.
The herpes virus, both HSV1 and HSV2 (responsible for genital herpes) are both neurotropic and neuro-invasive, meaning they persist in the body by becoming latent and hiding from the immune system in the cell bodies of neurons. After the initial or primary infection, the virus in a nerve cell becomes active and is transported via the neuron’s axon to the skin, where virus replication and shedding occur and cause new sores. HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia, e.g. HSV-1 tends to reside in the trigeminal ganglia, while HSV-2 tends to reside in the sacra ganglia and express “latency Associated Transcript (LTA) RNA. LAT is known to regulate the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences or “outbreaks” characteristic of non-latency. Whether or not recurrences are noticeable (symptomatic), viral shedding occurs to produce further infections in the victim or a new host, through contact.
In the presence of a certain gene variation (APOE-epsilon4 allele carriers), there is more chance of developing AD in the presence of HSV-1 and aged or inactive brain neurons. The mechanism that the virus degenerates the brain cells and causing AD is by recruiting cell membranes from the host containing amyloid precursor protein (APP), and consequently leads to deposition of amyloid plaques in the brain, replacing neurons. According to some studies, without the presence of the above-mentioned gene allele, HSV-1 and aged or inactive brain, such damaging or neurodegenerative process would not occur in the brain and there is low or no risk of developing Alzheimer’s. A more recent prospective study published in 2008 with a cohort of 591 subjects showed a statistically significant difference between patients with antibodies indicating recent reactivation of HSV and those without these antibodies in the incidence of Alzheimer’s disease, without direct correlation to the APOE-epsilon4 allele. In 2011 Manchester University scientists showed that treating HSV1-infected cells with antiviral agents decreased the accumulation of β-amyloid and P-tau, and also decreased HSV-1 replication.
While there is a strong link between HSV1 and the development of AD, it seems that the herpes simplex virus would not lead to the development of Alzheimer’s in every brain that it invades. A recent study by Wozniak research team in 2009 have showed that while in Alzheimer’s disease brains, 90% of the plaques contained the viral DNA and 72% of the DNA was associated with plaques, the control aged normal brains also contained amyloid plaques, though at a lower frequency, and 80% of plaques contained herpes simplex virus type 1 DNA, though only 24% of the viral DNA was plaque-associated. These researchers have suggested that “this is because in aged normal individuals, there is a lesser production and/or greater removal of beta-amyloid (Abeta), so that less of the viral DNA is seen to be associated with Abeta in the brain.” Therefore as it was stressed earlier, HSV1 can only lead to AD in the presence of APOE-4 gene plus aged or inactive brain.
The complex mechanism that HSV1 or any other possible virus invades the human body and the brain is worth detailing. Viruses can be conceptualized as self-replicating multiprotein assemblies, containing coding nucleic acids. Viruses have evolved to exploit host cellular components including enzymes to ensure their replicative life cycle. New findings indicate that also “viral capsid proteins” recruit host factors to accelerate their assembly. These assembly machines are RNA-containing multiprotein complexes whose composition is governed by allosteric sites. In the event of viral infection, the assembly machines are recruited to support the virus over the host and are modified to achieve that goal. In the case of viral infection, the assembly machines have been modified by the virus to meet the virus’ need for rapid capsid assembly rather than host homeostasis. In the case of the neurodegenerative diseases, it is the monomers and/or low n oligomers of the so-called aggregated proteins that are substrates of assembly machines. Examples for substrates are amyloid peptide and tau in Alzheimer’s disease, synuclein in Parkinson’s disease, prions in the prion diseases, and others.
Recently, findings comprising various viral families suggest that the cellular pathway to capsid assembly may be substantially different from the foundational self-assembly models that conform to the minimum requirements of thermodynamics. Indeed, without such catalytic “add ons” viral propagation might not be possible, given the obstacles not only of cytoplasmic crowding but also of innate immune mechanisms. Specifically, it has been suggested that capsid assembly is accelerated by transient formation of virus-recruited multiprotein complexes with enzymatic activity that serve as “assembly machines” to accelerate capsid formation. This catalyzed viral capsid assembly is an energy-dependent process, and host protein factors seem to play a major. In summary, surprising similarities in the cellular biology of virus capsid assembly and endogenous protein assembly suggest that cellular host factors, i.e. assembly machines, assist in and accelerate protein multimerization. Through their rapid generation cycles compared to their host cells, viruses have identified and exploited cell-resident macromolecules provided by host proteins used them to their advantage, i.e. fast and stable virus replication including capsid assembly.
Dr.Mostafa Showraki, MD, FRCPC Lecturer, School of Medicine, University of Toronto,Author: “ADHD:Revisited” Book/ “adhdrevisited.com”/”medicinerevisited.com”
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