Abstract
Alzheimer’s disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer’s disease is characterized by amyloid-beta and hyperphosphorylated tau, which are necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical benefits. Recent advances in fundamental research have indicated that neuroinflammation plays an important pathological role in AD. Damage- and pathogen-associated molecular patterns in the brain induce neuroinflammation and inflammasome activation, causing caspase-1-dependent glial and neuronal cell death. These waste products in the brain are eliminated by the glymphatic system via perivascular spaces, the blood-brain barrier, and the blood–cerebrospinal fluid barrier. Age-related vascular dysfunction is associated with an impairment of clearance and barrier functions, leading to neuroinflammation. The proteins involved in waste clearance in the brain and peripheral circulation may be potential biomarkers and drug targets in the early stages of cognitive impairment. This short review focuses on waste clearance dysfunction in AD pathobiology and discusses the improvement of waste clearance as an early intervention in prodromal AD and preclinical stages of dementia.
Highlights
Dementia is one of the most economically burdensome diseases in families as it is a long-term illness causing disability in daily life
Late-onset Alzheimer’s disease (AD), which occurs in people aged 65 years and above, has continuous progression from the preclinical stage without clinical symptoms to the pre-dementia stage, mild cognitive impairment (MCI), and AD with disability in daily life
Recent studies on brain waste clearance have revealed that the impaired glymphatic system and dysfunction of the blood–cerebrospinal fluid (CSF) barrier (BCSFB) and blood-brain barrier (BBB) resulted in the accumulation of waste following neuroinflammation in AD pathogenesis [13,33–35]
Summary
Dementia is one of the most economically burdensome diseases in families as it is a long-term illness causing disability in daily life. Brain wastes, including the aggregates described above, are thought to be eliminated from the parenchyma using both the glymphatic system [13] and blood–cerebrospinal fluid (CSF) barrier at the choroid plexus (CP) This mini-review describes the recent advances in AD pathobiology, focusing on waste clearance in the brain and possible strategies for the intervention and prevention of AD. As observed in autopsied AD brains, Aβ, which is produced from the amyloid precursor protein (APP) by the sequential cleavage of β- and γ-secretases, forms senile plaques It is a major pathogenic factor as its production increases in hereditary AD. The priming signals include lipopolysaccharide, bacterial pathogens, toxins, and double-stranded DNA These pathogen-and host-derived signals induce innate immunity and activate nuclear factor-kappa B (NF-κB) signaling, resulting in the production of Aβ and inflammatory cytokines [18,19].
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