Amyloid Beta in Aging and Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD), is a progressive neurodegenerative disease that affects behavior, thinking, learning, and memory in elderly individuals. AD occurs in two forms, early onset familial and late-onset sporadic; genetic mutations in PS1, PS2, and APP genes cause early onset familial AD, and a combination of lifestyle, environment and genetic factors causes the late-onset sporadic form of the disease. However, accelerated disease progression is noticed in patients with familial AD. Disease-causing pathological changes are synaptic damage, and mitochondrial structural and functional changes, in addition to increased production and accumulation of phosphorylated tau (p-tau), and amyloid beta (Aβ) in the affected brain regions in AD patients. Aβ is a peptide derived from amyloid precursor protein (APP) by proteolytic cleavage of beta and gamma secretases. APP is a glycoprotein that plays a significant role in maintaining neuronal homeostasis like signaling, neuronal development, and intracellular transport. Aβ is reported to have both protective and toxic effects in neurons. The purpose of our article is to summarize recent developments of Aβ and its association with synapses, mitochondria, microglia, astrocytes, and its interaction with p-tau. Our article also covers the therapeutic strategies that reduce Aβ toxicities in disease progression and discusses the reasons for the failures of Aβ therapeutics.

The Rat Brain Transcriptome: From Infancy to Aging and Sporadic Alzheimer’s Disease-like Pathology

“…The expression profile of genes associated with APP processing is downregulated in the brain of OXYS rats in the early postnatal period. Growing data on APP and Aβ suggests that they perform important physiological functions in the brain; the complete absence of the App gene in transgenic mice causes severe neurological deficits [ 40 ]. Some studies provide strong evidence that a decrease in Aβ clearance or a decrease in phagocytosis by microglia—rather than an Aβ peptide overproduction by cleavage of the APP—may be involved in AD [ 41 ].…”

“…Recently, it was revealed that patients with low levels of ABCA7 develop AD neuropathology at a younger age, those with intermediate ABCA7 amounts develop it later, and the patients who developed it very late have high ABCA7 levels, just as the youngest controls, suggesting that ABCA7 acts as a blocker of AD in the early stage of this disease [ 44 ]. Lipid composition of cellular membranes can influence secretase activities and then APP processing and Aβ synthesis; therefore, it can be hypothesized that ABCA7 levels and functioning can directly modulate APP processing and subsequently Aβ production [ 40 ].…”

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

“…In another recent article, Evgrafova et al have demonstrated thermoresponsive polymers varying in hydrophilicity/hydrophobicity ratio to selectively modulate Aβ aggregation kinetics [ 129 ]. Monoclonal antibodies (mAbs) directed against Aβ (bapineuzumab, crenezumab, solanezumab, and aducanumab) caused a lower incidence of AD [ 130 ]. However, increasing dosage in the later period of AD might have a negative impact on the trial results; in particular, antibodies may show off-target cross-reactivity [ 131 ].…”

Therapeutics of Alzheimer’s Disease: Recent Developments

“…Although good sleep plays a significant role in restoring brain functions and retaining memory, sleep is a critical factor in AD progression. The evidence of various studies has shown that sleep leads to changes in cell structure and affects the Aβ clearance mechanism [ 140 ]. Alzheimer’s patients show a significant disturbance in their circadian sleep–wake cycles, compared to similar-aged healthy individuals.…”