Alzheimer’s Disease and SARS-CoV-2: Pathophysiological Analysis and Social Context

Abstract

The COVID-19 pandemic has proven to be a challenge for healthcare systems, especially in terms of the care of patients with Alzheimer’s disease (AD). Age is one of the major risk factors for severe forms of COVID-19, most probably due to the presence of comorbidities and inflammations. It is known that SARS-CoV-2 invades nerve endings and olfactory nerves through the binding of the spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor. This interaction triggers an inflammatory cascade that results in cognitive impairment. In turn, the isoform of apolipoprotein-E4 (APOE-4ε) in AD is a risk factor for increased neuroinflammation through microglia activation, increased oxidative stress, and neurodegeneration. AD and SARS-CoV-2 are associated with increases in levels of inflammatory markers, as well as increases in levels of APOE-4ε, ACE2 and oxidative stress. Thus, there is a synergistic relationship between AD and SARS-CoV-2. In addition, the social isolation and other health measures resulting from the pandemic have led to a higher level of anxiety and depression among AD patients, a situation which may lead to a decline in cognitive function. Therefore, there is a need to develop strategies for keeping the patient calm but active.

Endogenous miRNA-Based Innate-Immunity against SARS-CoV-2 Invasion of the Brain

“…miRNA-146a is also significantly up-regulated in AD and PrD [ 2 , 16 , 57 , 58 ]. Interestingly, up to ~35% of all COVID-19 patients experience neurological and/or neuropsychiatric symptoms, and a pre-existing diagnosis of AD continues to predict the highest risk for COVID-19 yet identified, with the highest mortality among the most advanced cases and the most elderly of AD patients [ 5 , 62 , 63 , 64 , 65 , 66 , 67 ]. SARS-CoV-2 may potentiate the severity of neurological and neurocognitive deficits in patients already afflicted with other lethal neurodegenerative disorders such as AD and PrD [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].…”

“…Interestingly, up to ~35% of all COVID-19 patients experience neurological and/or neuropsychiatric symptoms, and a pre-existing diagnosis of AD continues to predict the highest risk for COVID-19 yet identified, with the highest mortality among the most advanced cases and the most elderly of AD patients [ 5 , 62 , 63 , 64 , 65 , 66 , 67 ]. SARS-CoV-2 may potentiate the severity of neurological and neurocognitive deficits in patients already afflicted with other lethal neurodegenerative disorders such as AD and PrD [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. Accordingly, the basal miRNA composition of the AD and/or COVID-19 patient and the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 continue to encompass critical health care directives and provide a compelling rationale for the careful monitoring of COVID-19 patients across the entire infection spectrum.…”

“…The widely observed variance in miRNA abundance, speciation, and complexity in normal, healthy aging in individuals defines in part what particular miRNA species are present, and specific patterns of miRNA abundance appear to have an impact on the particular physiological or pathophysiological status of individual susceptibility to both viral invasion and progressive inflammatory neurodegeneration [ 29 , 30 , 41 ]. Interestingly, a defined set of overexpressed miRNAs has been associated with an increased risk for the development of AD; therefore, it is reasonable to suggest that a specific set of host miRNAs and their specific cellular abundance may also confer susceptibility to, or protection against, ssRNA-based infectivity, viral-based infectious disease, and/or other forms of age-related inflammatory neurodegeneration [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].…”

“… Legend to Table 1 : Age Range (years) = age range of control tissues used in these studies (in years); Mean Age = average age of all superior temporal lobe neocortical tissue samples (STLN; Brodmann Area 22) in years plus or minus one standard deviation (SD); PMI = post-mortem interval (death to brain freezing interval at −81 °C); range in hours; numbers in the ‘total RNA quality’ column are indices for RNA spectral purity and represent the ratio of spectral absorbance of RNA scanned at 260 nm/280 nm, based on a total N = 27; the use of RNase-free plastic-ware and extraction reagents containing RNAsecure (Ambion-Invitrogen; ThermoFisher Scientific Inc., Waltham, MA, USA) ribonuclease inhibitors and short PMI brain tissues of the highest qualities obtainable yielded high-spectral quality total RNA, as analyzed using RNA LabChip Analysis Chips (Caliper Life Sciences Inc.-PerkinElmer, Waltham MA, USA;) and a 2100 Bioanalyzer (Agilent Technologies; Santa Clara, CA, USA) [ 68 , 69 ]; miRNA fractions were obtained from total STLN RNA using selective small RNA extraction and an miRNeasy Micro Kit [ 50 ] (Cat.No./ID: 217084; Qiagen, Germantown, MD, USA) and were analyzed on miRNA analytical arrays (proprietary MRA-1001-miRNA microfluidic chip analytical platform (LC Sciences Corporation, Houston, TX, USA; (accessed on 26 December 2022); data derived from [ 50 , 51 , 55 , 58 , 61 , 65 , 66 , 67 , 68 , 69 ]; see below and Table 2 ). …”

“… Legend to Table 2 : This table indicates the most abundant unique miRNAs detected in the human brain superior temporal lobe neocortex (STLN; Brodmann Area 22); abundances are ranked by miRNA numerical designation, based on pooled data from N = 27 short post-mortem interval (PMI) control tissues; data derived from [ 50 , 51 , 55 , 58 , 61 , 65 , 66 , 67 , 68 , 69 ]; this group included 9 males and 18 females, mean age 75.2 ± 9.5 years; all post-mortem intervals (PMIs; death to brain freezing at −81 °C) were less than 3.3 h (see Table 1 ); each of these miRNAs yielded high (≥3000) units of signal strength on LC Sciences miRNA analytical arrays Genechip (proprietary MRA-1001-miRNA microfluidic chip analytical platform; 2650 small non-coding RNAs (sncRNAs) were analyzed; LC Sciences Corporation, Houston, TX, USA; on 26 December 2022) and ranked as the 54 most abundant miRNAs detected in the superior temporal lobe neocortex; except for miRNAs listed here, all other miRNAs are at a significantly lower abundance; note that there is a relatively high basal abundance of the let-7a to let-7i group of miRNAs; also note that AD-abundant miRNAs such as miRNA-9, miRNA-30b, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155 exhibit high relative variability in mean abundance in control brains and are significantly up-regulated in AD brains; in human neuronal-glial (HNG) cells in primary culture, most of these same miRNAs are induced by the pro-inflammatory transcription factor NF-kB (p50/p65) [ 66 ]; these same miRNAs are up-regulated in AD brains, especially as AD progresses; superior temporal lobe-enriched miRNAs overlain in gray (and their mRNA targets) have been strongly implicated in AD [ 23 , 50 , 51 , 52 , 53 , 54 , 55 , 57 , 66 ]; miRNAs with a single asterisk such as miRNA-7, miRNA-9, miRNA-30b, miRNA-34a, miRNA-125b, and miRNA-146a are moderately abundant in control of the adult human superior temporal lobe neocortex (Brodmann Area 22); many of these same miRNAs are implicated in other infectious, inflammatory, and/or immunological diseases [ 11 , 12 , 23 , 24 , 25 , 26 , 27...…”