On a New Paradigm of the Development of Neurodegenerative Diseases by the Example of Alzheimer's Disease and Parkinson's Disease

The role of neuronal inflammation developing during the formation of amyloid plaques and Lewy bodies is investigated. The influence of various exogenous and endogenous factors on the development of neuroinflammation is established, but the role of various infectious agents in the development of this process is much less studied. Today, the existence of a universal trigger mechanism of the neurodegenerative process is obvious: a specific pathogen of a bacterial or viral nature (including long-term persistent in nervous tissue in a latent state), reactivating, penetrates into certain cerebral structures, where it is influenced by either A beta or resident macrophages of the central nervous system, which, in turn, are activated and induce the release of proinflammatory cytokines, leading to the development of neuronal inflammation, autophagy and neurodegeneration. The reactivation of latent infection, such as herpes, in APOE4 carriers significantly increases the risk of development of Alzheimer's disease. Class-II genes of the HLA locus (HLA II) may be related to the progression of neurodegenerative diseases. An increase in iron levels in the glia is induced by inflammation, which leads to neurodegeneration. Disruption of the homeostasis of redox-active metals, iron and copper, is an integral part of the pathogenesis of Alzheimer's disease and Parkinson's disease. The developing neuroinflammation leads to intensification of the processes of peroxidation, oxidation of metals and the development of ferroptosis.

Relation between apolipoprotein e in alzheimer's disease and sars-cov-2 and their treatment strategy: A review.

COVID-19, which primarily affects the pulmonary system, turned out to be a global pandemic, whereas the effects on other systems are still unknown. SARS-CoV-2, binds to angiotensin-converting enzyme 2 (ACE2) receptors in the lungs, causing pneumonia-like symptoms. The same ACE receptors are also present in organs other than the lungs. Therefore, there is a need to study the impact of coronavirus on other human body organs. Recently, UK Biobank reports on the genetic risk factor of the virus attack. A double mutation in the apolipoprotein E (APOE4) allele has shown a significant role in COVID-19. The same APOE4 mutation has already been proven to hold a key role in developing early-onset Alzheimer's disease (EOAD). Despite this data, Alzheimer's disease is believed to be a comorbidity of COVID-19. Previous virus attacks on the same viral family, Coronaviridae, produced neurological effects like neurodegeneration, neuronal inflammation, and other central nervous system-related dysfunctions. Since the long-term implications of COVID-19 are unknown, more research into the impact of the virus on the central nervous system is needed. Both COVID-19 and AD share a common genetic factor, so that AD patients may have a greater risk of SARS-CoV-2. Here, in this review, we have briefly discussed the role of APOE4 in the pathogenesis of AD and SARS-CoV-2, along with their treatment strategy, current scenario, and possible future directions.

The Unifying Hypothesis of Alzheimer's Disease: Heparan Sulfate Proteoglycans/Glycosaminoglycans Are Key as First Hypothesized Over 30 Years Ago.

The updated "Unifying Hypothesis of Alzheimer's disease" (AD) is described that links all the observed neuropathology in AD brain (i.e., plaques, tangles, and cerebrovascular amyloid deposits), as well as inflammation, genetic factors (involving ApoE), "AD-in-a-Dish" studies, beta-amyloid protein (Aß) as a microbial peptide; and theories that bacteria, gut microflora, gingivitis and viruses all play a role in the cause of AD. The common link is the early accumulation of heparan sulfate proteoglycans (HSPGs) and heparan sulfate glycosaminoglycans (GAGs). HS GAG accumulation and/or decreased HS GAG degradation is postulated to be the key initiating event. HS GAGs and highly sulfated macromolecules induce Aß 1-40 (but not 1-42) to form spherical congophilic maltese-cross star-like amyloid core deposits identical to those in the AD brain. Heparin/HS also induces tau protein to form paired helical filaments (PHFs). Increased sulfation and/or decreased degradation of HSPGs and HS GAGs that occur due to brain aging leads to the formation of plaques and tangles in AD brain. Knockout of HS genes markedly reduce the accumulation of Aß fibrils in the brain demonstrating that HS GAGs are key. Bacteria and viruses all use cell surface HS GAGs for entry into cells, including SARS-CoV-2. Bacteria and viruses cause HS GAGs to rapidly increase to cause near-immediate aggregation of Aß fibrils. "AD-in-a-dish" studies use "Matrigel" as the underlying scaffold that spontaneously causes plaque, and then tangle formation in a dish. Matrigel mostly contains large amounts of perlecan, the same specific HSPG implicated in AD and amyloid disorders. Mucopolysaccharidoses caused by lack of specific HS GAG enzymes lead to massive accumulation of HS in lysosomal compartments in neurons and contribute to cognitive impairment in children. Neurons full of HS demonstrate marked accumulation and fibrillization of Aß, tau, α-synuclein, and prion protein (PrP) in mucopolysaccharidosis animal models demonstrating that HS GAG accumulation is a precursor to Aß accumulation in neurons. Brain aging leads to changes in HSPGs, including newly identified splice variants leading to increased HS GAG sulfation in the AD brain. All of these events lead to the new "Unifying Hypothesis of Alzheimer's disease" that further implicates HSPGs /HS GAGs as key (as first hypothesized by Snow and Wight in 1989).