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.

Keywords: Alzheimer’s disease; amyloid beta; amyloid precursor protein; mitochondria; neurofibrillary tangle; therapeutics.

Figure 1

Potential risk factors for Alzheimer’s disease. There are two types of risk factors for Alzheimer’s disease that are modifiable and non-modifiable factors. Modifiable risk factors mainly include diseases, brain injuries, unhealthy lifestyles, and environmental factors, and non-modifiable factors include age, gender, family history, and genetics.

Figure 2

Top ten countries with the highest death rate due to dementia. The data is collected from the World health organization 2020, and the reported death rate is age-standardized.

Figure 3

Amyloid precursor protein (APP) processing. Two proteolytic pathways, amyloidogenic and non-amyloidogenic processing, exist for APP processing. The amyloidogenic pathway involves β and γ secretases and releases N-terminal soluble APPβ fragments, and Aβ peptides in the extracellular region. The non-amyloidogenic involves α and γ secretases and releases N-terminal APPα fragments, and P3 peptides in the extracellular region. Both proteolytic pathways release APP intracellular domain (AICD) fragments intracellularly.

Figure 4

The physiological and pathological role of amyloid beta in the human brain.

Figure 5

Amyloid beta and tau protein at the synapse. In Alzheimer’s disease, amyloid precursor protein is processed into amyloid beta peptides that accumulate inside and outside the neuronal cells and form plaques. The deposition of amyloid plaques in the vicinity of the synapse causes synaptic loss and dysfunction. Moreover, glutamate recycling is also dysregulated in the presence of pathological amyloid beta levels in neurons. The soluble, hyperphosphorylated tau protein can directly move across the plasma membrane, or by another mechanism where the formation of nanotubules helps the translocation of tau intracellularly. The synergetic pathology of Aβ and tau at synapse causes synaptic loss and dysfunction.

Figure 6

Pathogenesis of Alzheimer’s disease. The multiple factors responsible for the progression of Alzheimer’s disease include amyloid beta plaques, and tau neurofibrillary tangles formation leading to neuronal loss, activation of microglia (found to be concentrated in the vicinity of amyloid plaques) that leads to neuroinflammation, mitochondrial dysfunction, synaptic loss, and dysregulation of calcium homeostasis. The accumulation of Aβ in Alzheimer’s brain disturbs synapsis which leads to postsynaptic hyperexcitability. The hyperexcitability of neurons causes dysregulation of calcium homeostasis and an increase in the production of reactive oxygen species.

Figure 7

Amyloid beta therapeutic strategies. The commonly used therapeutic strategies for AD that targets amyloid beta are amyloid monoclonal antibodies, aggregation inhibitors (e.g., E16, E18), BACE inhibitors (e.g., CNP 520, MK8931, RIPK1), γ-secretase modulators, and calcium channel blockers (isradipine, nimodipine, verapamil, diltiazem).