A recent review from Schichun Tu and colleagues entitled “Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease” was published this week in the journal Molecular Neurodegeneration. The aim of the study was to discuss the state of current evidence suggesting that the synaptic loss found in Alzheimer’s disease (AD) is induced by soluble amyloid-beta peptide (Abeta, Aβ) oligomers.
Alzheimer’s disease (AD) is characterized by a gradual decline in cognitive functioning, occurring in people aged 65 years or above, with a progressive decline in memory, thinking, language, and learning capacity.
The Alzheimer’s Association estimates that 5.4 million Americans have the disease and that one in eight older people will develop AD. There is no cure for AD and available treatments only target temporary memory and cognitive functioning improvements. However, an understanding of the underlying mechanisms that are involved in the pathogenesis of AD may help further pharmacological inputs.
AD is caused by a decline and death of neurons that it is initiated in the hippocampus, the brain region involved in memory and learning. With the progression of the disease, the death of the neurons affects the entire brain.
Amyloid beta is a peptide that is an abnormal proteolytic by product of the transmembrane protein amyloid precursor protein (APP). Amyloid beta oligomers (ADDLs) are thought to cause synaptic loss and gradual cognitive decline in AD, while monomers are soluble and contain short regions of beta sheet at sufficiently high concentration.
These fibrils deposit outside neurons in dense formations known as senile or neuritic plaques in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy. In AD there is an overaggregation of tau protein, that acts to stabilize microtubules in the cell cytoskeleton and it regulated by phosphorylation. In AD patients, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.
In this review, the authors discuss current evidence of studies in animal models that found that e oligomeric AB plays a key role in the synaptic dysfunction and cognitive deficits involved in AD through different pathways. These pathways include glutamate receptors and their downstream pathways, abnormal elevation of extrasynaptic glutamate levels and subsequent eNMDAR-mediated excitotoxicity, tau hyperphosphorylation and impaired mitcochondria. However, the authors debate the lack of evidence of these findings in humans.
Schichun Tu and colleagues concluded that although Aβ-induced synaptic and phosphor-tau dysfunctions found in AD involve multiple pathways, evidence shows the knowledge of these implicated mechanisms may help to develop therapeutics for the prevention and treatment of AD.