A deep dive into the hallmarks defining Alzheimer’s disease

The progressive decline in neurocognition, resulting in a detrimental effect on one’s

activities of daily living, is referred to as dementia. It typically affects people over the age of 65. Multiple theories have been proposed to explain the pathogenesis of Alzheimer’s

disease (AD), including the buildup of amyloid plaques in the brain and the formation of

neurofibrillary tangles (NFT) in cells. Understanding the pathophysiology of AD is imperative to the development of therapeutic strategies. Therefore, this article will outline the major hallmarks and mechanisms of AD.

Hallmark 1: amyloid plaques

One of the most widely accepted hypotheses for AD is the accumulation of amyloid beta

protein (Aβ) in the brain. Aβ is a 4.2 kDa peptide consisting of approximately 40–42 amino

acids, originating from a precursor molecule called amyloid precursor protein. This process, defined as amyloidosis, is strongly linked to brain aging and neurocognitive decline.

How do the amyloid plaques form? See Figure 1.

Reasons for the accumulation of amyloid plaques:

• Decreased autophagy:

Amyloid proteins are abnormally folded proteins. Autophagy in the brain is primarily carried out by neuronal and glial cells, involving key structures known as autophagosomes and lysosomes. When autophagy becomes downregulated, the metabolism of Aβ is impaired, eventually resulting in plaque buildup.

• Overproduction of acetylcholinesterase (AChE):

Acetylcholine (Ach) is the primary neurotransmitter involved in memory, awareness, and learning. Overproduction of ACHE by astrocytes into the synaptic cleft can lead to excessive breakdown of Ach, with detrimental effects on cognition.

• Reduced brain perfusion:

Blood flow delivers necessary nutrients and oxygen for cellular function. Reduced perfusion can lead to “intracerebral starvation”, depriving cells of the energy needed to clear Aβ.

• Reduced expression of low-density lipoprotein receptor-related protein 1:

Low-density lipoprotein receptor-related protein 1 (LRP1) receptors are abundant in the central nervous system under normal conditions. They are involved in speeding up the metabolic pathway of Aβ by binding to its precursor and transporting them from the central nervous system into the blood, thereby reducing buildup. Reduced LRP1 expression can hinder this process, leading to amyloid buildup.

• Increased expression of the receptor for advanced glycation end products (RAGE):

RAGE is expressed on the endothelial cells of the BBB, and its interaction with Aβ facilitates the entry of Aβ into the brain.

Hallmark 2: neurofibrillary tangles

See Figure 2

Neurofibrillary tangles are excessive accumulations of tau protein. Microtubules typically

support neurons by guiding nutrients from the soma (cell body) to the axons. Furthermore,

tau proteins stabilise these microtubules. In AD, signalling pathways involving phosphorylation and dephosphorylation cause tau proteins to detach from microtubules and stick to each other, eventually forming tangles. This results in a disruption in synaptic communication of action potentials. However, the exact mechanism remains unclear.

Recent studies suggest an interaction between Aβ and tau, where Aβ can cause tau to

misfold and aggregate, forming neurofibrillary tangles inside brain cells. Both Aβ and tau can self-propagate, spreading their toxic effects throughout the brain. This creates a vicious cycle, where Aβ promotes tau toxicity, and toxic tau can further exacerbate the harmful effects of Aβ, ultimately causing significant damage to synapses and neurons in AD.

Hallmark 3: neuroinflammation

Microglia are the primary phagocytes in the central nervous system. They can be activated

by dead cells and protein plaques, where they initiate the innate immune response. This

involves the release of chemokines to attract other white blood cells and the activation of

the complement system which is a group of proteins involved in initiating inflammatory

pathways to fight pathogens. In AD, microglia bind to Aβ via various receptors. Due to the

substantial accumulation of Aβ, microglia are chronically activated, leading to sustained

immune responses and neuroinflammation.

Conclusion

The contributions of amyloid beta plaques, neurofibrillary tangles and chronic

neuroinflammation provide a framework for understanding the pathophysiology of AD. AD

is a highly complex condition with unclear mechanisms. This calls for the need of continued research in the area as it is crucial for the development of effective treatments.

Written by Blessing Amo-Konadu

Related articles: Alzheimer's disease (an overview) / CRISPR-Cas9 to potentially treat AD

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