The clinical symptoms and signs of Alzheimer’s disease (AD) result from abnormalities associated with neuronal dysfunction and cell death in specific brain regions which are important in memory and cognitive functions. Damaged circuits include the basal forebrain cholinergic system, amygdala, hippocampus, entorhinal and limbic cortex, and specific regions of neocortex. Major pathological hallmarks of AD are extracellular amyloid plaques and intracelluar neurofibrillary tangles. Neurofibrillary tangles are composed of phosphorylated and aggregated forms of tau which is assembled into the paired helical filaments, and amyloid plaques are composed of Aβ peptides existing in the extracellular space in β-pleated sheet conformations.
Amyiold plaques are critical for the diagnosis of AD and the major component of amyloid plauqes is amyoid-β (Aβ) peptide. Aggregation of the amyloid-β (Aβ) peptide in the extracellular space of the brain is critical in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced by neurons and released into the brain interstitial fluid (ISF), a process regulated by synaptic activity. The process of Aβ aggregation is believed to be concentration dependent in the extracellular space. Aβ is a peptide fragment, principally 40 or 42 amino acids long, that is proteolytically cleaved from a large precursor polypeptide, amyloid-β precursor protein (APP). Once generated, Aβ can exist in a soluble monomeric state or potentially in oligomeric forms or fibrils. There is strong evidence that Aβ may play a central role in AD. First, all patients with AD accumulate deposits of Aβ42 and Aβ40 in vulnerable brain regions. Second, most autosomal dominant mutations in APP and in the presenilins alter APP processing which results in more production of Aβ42. Third, some APP mutations are in the Aβ region and cause altered fibrillogenesis or clearance of Aβ without affecting APP processing. Down syndrome individuals who are trisomic for APP as well as other genes develop AD pathology in their early ages. Fourth, there are patients who have triplication of APP that develop early onset AD with cerebral amyloid angiopathy (CAA). This evidence suggests that Aβ may be central to the disease process. Consequently, recent therapeutic strategies have been designed to reduce production of Aβ, enhance clearance of Aβ, and prevent formation of oligomeric species of Aβ which damage neurons and synapses.
Aβ is cleaved from amyloid precursor protein (APP) by β and γ-secretases and is released from mostly neurons into the brain interstitial fluid (ISF). This event happens in the healthy brain throughout life. During AD progression, soluble Aβ peptides start to aggregate and accumulate in the toxic forms such as oligomers, fibrils, and plaques. It is not identified yet whether the seed of amyloid plaques originates extracellularly or intracellulary, but there is a evidence suggesting that initial step for amyoid plauqes formation and growth could occur in the extracellular space. Regardless of the origin of amyloid plaques, Aβ peptides in the ISF seem to be important in amyloid plaque formation, and the process of Aβ aggregation is believed to be concentration dependent in the brain extracellular space. Therefore, understanding how Aβ is regulated in the brain ISF is important in understanding AD pathogenesis.
Accumulating evidence suggests a direct relationship between neuronal/synaptic activity and Aβ metabolism. APP is transported from entorhinal cortex to the hippocampal formation via the perforant pathway, and lesioning this pathway results in substantially less Aβ deposition in the hippocampus in human APP transgenic mice. Decreasing neuronal/synaptic activity over 24-48 hours reduces steady-state Aβ levels in media using hippocampal slice cultures in human APP transgenic mice. Using an in vivo microdialysis technique simultaneously with field potential recordings, Cirrito et al. showed that Aβ levels in the brain interstitial fluid are directly influenced by synaptic activity and synaptic vesicle release over minutes to hours.
Reference:
Jae-Eun Kang. AMYLOID-p REGULATION IN THE BRAIN INTERSTITIAL FLUID OF A MOUSE MODEL OF ALZHEIMER’S DISEASE