In a recent review published within the Journal of Neurochemistry, researchers evaluate the impact of the coronavirus disease 2019 (COVID-19) on Alzheimer’s disease (AD) pathology.
Study: COVID-19 and the impact on Alzheimer’s disease pathology. Image Credit: alexialex / Shutterstock.com
Background
COVID-19 primarily affects older individuals with medical disorders that compromise their immunity. The various neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection indicate that the virus could impact the brain in several ways.
Previous studies have reported that viral infections may lead to neurodegeneration. Since COVID-19 and AD share risk aspects and pathological characteristics, there have been significant public health concerns regarding the neurological impact of SARS-CoV-2 infection and its probable contribution to AD onset and progression through inflammation.
Pathogenesis and risk aspects of AD and COVID-19
AD is characterised by increases in amyloid plaques, neurofibrillary tangles (NFTs), neuroinflammation, and neuronal loss. Extracellular amyloid plaques, that are predominant within the hippocampus and neocortex, develop resulting from amyloid beta (Aβ) peptide accumulation, which ends up from amyloidogenic processing and amyloid precursor protein (APP) cleavage by proteolytic enzymes equivalent to beta- and gamma-secretase.
NFTs are abnormal filaments comprising misfolded and abnormally hyperphosphorylated tau proteins that accumulate in axons and dendrites and result in neuronal loss. NFT accumulation occurs within the entorhinal cortex, CA1, and subiculum hippocampal regions. Aβ accumulation leads to glial cell activation and inflammation.
Astrocytes are essentially the most abundant glial cell type within the central nervous system (CNS). Upon activation, astrocytes and microglia secrete pro-inflammatory cytokines equivalent to tissue necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-1 (IL-1), and IL-6. The discharge of those cytokines can induce neuronal damage and Aβ production, which is related to elevated Aβ42/Aβ40 ratios, tau pathology, and neurotoxicity.
Risk aspects for COVID-19 include age and certain comorbidities like diabetes, obesity, heart problems, and hypertension. Previous studies have indicated pre-existing dementia is a distinguished risk factor for COVID-19 severity and mortality. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, also can enhance COVID-19 risk.
SARS-CoV-2 infections, neurodegeneration, and Alzheimer’s disease
Viral infections equivalent to COVID-19 are related to an increased risk of cognitive decline and neurodegenerative diseases. SARS-CoV-2 has amyloidogenic properties and might initiate amyloid aggregation. SARS-CoV-2 infection can increase Aβ42 protein neurotoxicity in brain cells, impair Aβ42 clearance from the blood, and enhance amyloid protein aggregation within the cerebrospinal fluid (CSF).
The presence of Aβ42 can enhance SARS-CoV-2 spike (S) protein-angiotensin-converting enzyme 2 (ACE2) interactions, thus facilitating entry into the host and stimulating the discharge of inflammatory cytokines like IL-1β and IL-6, that are linked to Aβ deposition and impaired neurogenesis within the hippocampus.
ACE2 elevation in AD murine models reduces Aβ42 accumulation within the hippocampus, reduces hyperphosphorylated tau protein and inflammatory cytokine levels in brain cells, and improves cognition. Due to this fact, ACE2 inhibition, which has been observed during SARS-CoV-2 infection, may worsen AD-related neuroinflammation and pathology.
ACE2 regulates brain-derived neurotrophic factor (BDNF) levels, essential for neurogenesis, cognition, and development. Reduced BDNF can increase tau protein phosphorylation, neuroinflammation, and neurodegeneration amongst SARS-CoV-2-infected individuals. Researchers have identified ACE2-expressing CNS cells equivalent to microglia, neurons, astrocytes, and oligodendrocytes as probable interventional targets.
Experimental coronavirus infections within the CNS of mice have stimulated astrocytes and microglia related to pro-inflammatory cytokine and chemokine release that activate each the innate and adaptive immunological systems. SARS-CoV-2-induced microglial activation, partly regulated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome, impairs Aβ protein clearance and increases neuroinflammation-related gene expression.
Post-mortem evaluation of brains from SARS-CoV-2-infected individuals exhibits gliosis and immune cell accumulation related to axonal injury and blood-brain barrier (BBB) disruption and, in consequence, increased capillary permeability and endothelial damage. Elevated serological neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels amongst moderate-to-severe COVID-19 patients indicate neuronal and astrocytic injury.
One yr after severe COVID-19, reduced axonal density has been reported within the superior longitudinal fasciculus corpus callosum and corona radiata of the brain. Alterations within the olfactory cortical and limbic systems, including tissue injury and reduced gray matter thickness, have also been reported.
Conclusions
Overall, the study findings highlight the link between COVID-19 and AD, with SARS-CoV-2 infections linked to neuroinflammation, neurodegeneration, and long-term cognitive impairment. These findings indicate that each COVID-19 and AD have synergistic effects; nonetheless, further research is required to elucidate their long-term implications.