Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment

Abstract

Alzheimer’s disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.

Association of Hypothyroidism and the Risk of Cognitive Dysfunction: A Meta-Analysis

“…It is reported [63] that elevated exosomal ApoE4 demonstrated a significant inverse correlation with the serum level of thyroid hormones and cognitive function. It is thyroid hormone levels, not thyroid-stimulating hormone levels, that are associated with cognition dysfunction, so is it possible to speculate that age-related TSH elevations are a form of compensation to maintain normal thyroid hormone levels to ensure normal cognitive function requirements?…”

“…Reference [63] suggested a possible mechanism for the relationship between hypothyroidism and cognitive impairment. Ageing-associated hypothyroidism and acute thyroidectomy increased the transport of liver-derived ApoE4 to exosomes and into the brain, where ApoE4 activated the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing the cholesterol level in neural cells.…”

Bidirectional Communication Between the Brain and Other Organs: The Role of Extracellular Vesicles

“…Age-related thyroid deficiency can enhance exosomal transport of ApoE4 from liver to brain, which causes AD-related dementia and neuronal dysfunction in ApoE4 allele carriers. These changes also coincide with ApoE4-induced activation of the NLRP3 inflammasome and pyroptosis of neurons (Zhang et al 2022a , b ). Exosomes isolated from serum of rats with hepatic ischemia–reperfusion injury may induce neuronal damage in the hippocampus and cortex, which is associated with the NLRP3 inflammasome and caspase-1-dependent pyroptosis (Zhang et al 2019 ).…”

Neural stem/progenitor cell‐derived extracellular vesicles: A novel therapy for neurological diseases and beyond

“…To date, NSC transplantation‐based therapy has been widely investigated for its feasibility and effectiveness to rescue the pathological changes in neurological diseases using various disease animal models. 18 , 35 , 36 , 37 NSCs exhibit the capacity to replace degenerating or damaged neurons and secrete neuroprotective and immunomodulatory substances such as brain‐derived neurotrophic factor (BDNF) and glia‐derived neurotrophic factor after transplantation. 38 , 39 , 40 For example, NSC transplantation has been reported to improve the cognitive functions and enhance synaptogenesis in AD models, 41 attenuate induced turning behavior in PD models, 42 preserve motor neurons and muscle innervation in ALS models, 43 and enhance dendrite branching and corticospinal tract projections in stroke mice.…”

“…To date, NSC transplantation‐based therapy has been widely investigated for its feasibility and effectiveness to rescue the pathological changes in neurological diseases using various disease animal models 18,35–37 . NSCs exhibit the capacity to replace degenerating or damaged neurons and secrete neuroprotective and immunomodulatory substances such as brain‐derived neurotrophic factor (BDNF) and glia‐derived neurotrophic factor after transplantation 38–40 .…”