by Keanna Bantay
Alzheimer’s disease is a common type of dementia that can result in a decline of cognitive functions such as language, attention, comprehension, memory, and judgment. It can be a hindrance in daily activities, and independence, and cannot be cured, but treatment may help. Common symptoms are short-term memory loss, impairment in judgment, language disorder, agitation, and sleep disturbances (Kumar, Sidhu, and Goyal). AD can affect lifestyle by removing the abilities of reasoning and memory. Alzheimer’s disease is grouped in amyloidosis which are disorders with an accumulation of misfolded and unfolded proteins. Often there is an accumulation of Aβ (amyloid-beta peptide) in the medial temporal lobe and neocortical structures. Alzheimer’s disease is often characterized by neuritic plaques, neurofibrillary tangles, and Aβ oligomers. Tau proteins and amyloids play a significant role in Alzheimer’s disease. It can assist in forming neuritic plaques, neurofibrillary tangles, and Aβ oligomers which can cause toxicity. Through this paper, we will explore how neuritic plaques, neurofibrillary tangles, and Aβ oligomers form. We will study the finding of a kinase protein associated with Alzheimer’s disease and the impact of Asp664.
Misfolded Proteins
When there is a neurodivergent disease, in the transition of target proteins from α-helix to a β-sheet form they obtain toxicity. Transitioning from α-helix to a β-sheet is often seen in amyloid deposits and physiological functions becoming pathological. These transitions can encourage protein aggregation and release hydrophobic amino acid residues. Toxic proteins may interact with other native proteins and transition them into a toxic state. These new toxic proteins may repeat this cycle with other native proteins resulting in more toxicity and detrimental damage. Proteins require their amino acids to be folded correctly in order to function properly, therefore, if the protein is misfolded it can form insoluble aggregates and become toxic. Without the proper clearance, misfolded proteins may accumulate resulting in Alzheimer’s disease.
In diseases, hIAPP misfoldings are found and it can be toxic when combined with human islet β-cells. Membranes can affect hIAPP misfolding in two ways, first being targeted by hIAPP oligomers to create toxicity. Second, membranes can help speed up the chemical reaction of misfolding when hIAPP and negatively charged membranes interact. A misfolding with a membrane involved happens through an α-helical intermediate and accelerates based on ionic strength. Researchers Apostolidou, Jayasinghe, and Langen used EPR spectroscopy and molecular modeling to further investigate α-helical, membrane-bound hIAPP. In their findings, residues 20-29, an amyloidogenic region of hIAPP, encourage the formation of secondary structure and cause aggregation. Due to membrane interactions, residues 21 and 22 are badly folded which is of importance because membrane interactions help form the β-sheet structure. With the additional factor of membrane interactions transforming the process of hIAPP molecule encounters into a two-dimensional process, membrane-mediated hIAPP misfolding accelerates (Apostolidou).
Risk factors
A factor that can increase this is old age because, in the process of aging, we acquire more mutations and changes in our protein structures. Changes in our protein structure increase the chances of an accumulation of misfolded proteins. An environmental factor that can increase risk is substances that may affect mitochondrial function. Damage to the mitochondrial function can result in oxidative damage to proteins. There may also be genetic factors these mutations can affect the disease differently from the different mutations and combinations of the gene.
Neuritic plaques
Alois Alzheimer, a German psychiatrist, found amyloid plaques in the brain of his first patient who was experiencing memory loss. Alzheimer’s disease is often an accumulation of abnormal neuritic plaques which have a core of extracellular amyloid beta-peptide. These beta-amyloid peptides originate from an amyloid precursor and divide from APP through the proteases alpha, beta, and gamma-secretase. Through this cleavage, it can result in aggregated fibrillar amyloid proteins which are favored by Beta-amyloid 42 (Kumar, Sidhu, and Goyal). There may also be 40 or 42 aa long Aβ peptide fragments discharged which can combine and form into insoluble Aβ clumps and oligomers. These insoluble Aβ clumps and oligomers gather around neurons and can have toxic effects. Aβ directly affects neurotoxicity and neural function which can lead to cognitive impairments if plaques accumulate in the hippocampus, amygdala, and cerebral cortex.
Structure of brains and neurons of a healthy brain in comparison with an Alzheimer’s disease brain.
^1 Breijyeh, Zeinab, and Rafik Karaman. “Comprehensive Review on Alzheimer’s Disease: Causes and Treatment.” Molecules (Basel, Switzerland) vol. 25,24 5789. 8 Dec. 2020, doi:10.3390/molecules25245789
Neurofibrillary tangles
Neurofibrillary tangles formed by the protein tau are more associated with Alzheimer’s disease. Tau proteins support microtubule assembly but can become hyperphosphorylated from aggregation of extracellular beta-amyloid. As a result, tau aggregates form settling in neurons, twisting into paired helical filaments, and creating neurofibrillary tangles (Kumar, Sidhu, and Goyal). Accumulation of tangles in neural perikaryal cytoplasm, axons, and dendrites can reduce cytoskeletal microtubules and tubulin-associated proteins. The evolution of neurofibrillary tangles can be put into three stages, the first happening before it tangles. In this stage, accumulated phosphorylated tau proteins gather in the somatodendritic compartment without paired helical filaments forming. In the next stage, mature neurofibrillary tangles possess filament aggregation and a displaced nucleus in the periphery part of the soma. Lastly, they become extracellular tangles from filamentous tau protein causing a neuronal loss (Ashraf).
Neurofilaments are microfilaments located in the soma, axon, and dendrites. They support and regulate axons making them a large part of the neuronal cytoskeleton. Neurofibrillary tangles are groups of paired helically twisted filaments that occur in pyramidal cells and neurons. These may be neurofilaments or microtubules which form from intracellular hyperphosphorylation of tau protein. The twisted fibers of tau protein damage axonal support in the range of the cell body and many synapses. The purpose of tau protein is to support microtubules by binding to them. When a tau protein is hyperphosphorylated it can no longer support microtubules because it is unable to bind to it. As the tau protein is not binded, they will clump with each other creating neurofibrillary tangles. These neurofibrillary tangles eventually damage intercellular functions and have been linked with neuropsychiatric behaviors such as aggression (Ashraf).
Aβ oligomers
The failure of Aβ peptide clearance can lead to the accumulation of Aβ in brain arteries. These aggregate states of Aβ may be in the form of oligomers which would be small and soluble oligomers that can contain 5-6 monomeric units. Aβ oligomers with a smaller diameter are more likely to fuse with synaptic clefts causing neuronal and synaptic dysfunction. Oligomerization can happen when the concentration of Aβ increases and there is a higher Aβ42/Aβ40 ratio at the beginning of amyloid plaque formation. Consequently, there may be formation of Aβ deposits which can cause inflammatory responses, synaptic spine loss, and neuritic dystrophy. One of the greatest factors in Aβ induced toxicity is Aβ structure as the β-sheet is the dominant structure of Aβ oligomers (Ashraf).
Signal transduction
APP can generate neurotoxic β-amyloid peptides and a second neurotoxic peptide through Asp664. Researchers conducted a study to identify signaling mechanisms and to understand the contribution of Asp664. Through the study of comparing animals with Alzheimer’s disease, the researchers were able to discover a kinase protein that contributes to Alzheimer’s disease that was found more in platelet-derived growth factor B-chain promoter-driven APP transgenic mice that do not have a functional Asp664 caspase cleavage site. The researchers found differences between the platelet-derived growth factor B-chain promoter-driven APP transgenic mice and the platelet-derived growth factor B-chain promoter-driven APP transgenic mice with the absence of a functional Asp664.
The experiment was conducted using antibodies, human autopsy material, transgenic mouse lines, and western blots. Through immunohistochemical and immunoblotting studies on mice with Alzheimer-like neuropathology, an increase in active p21-activated kinases was observed in platelet-derived growth factor B-chain promoter-driven APP transgenic mice. From assessing hippocampal levels it is evident that a functional Asp664 cleavage site is required to increase active p21-activated kinases. Transgenic platelet-derived growth factor B-chain promoter-driven APP transgenic mice had greater p21-activated kinases activation and neurons with active p21-activated kinases. In comparison with transgenic mice possessing a mutated Asp664, there was no significant increase in p21-activated kinase activation or neurons with active p21-activated kinases.
To determine whether the PAK changes in platelet-derived growth factor B-chain promoter-driven APP transgenic mice applied to human AD, researchers used immunohistochemical labeling on subjects that were either neuropathologically normal, early AD changes, moderate AD neuropathology, or severe AD. In the subjects, there was a decrease in p21-activated kinase immunoreactivity. Other studies have found that a signaling mechanism of AD neuropathology is a functional cleavage of APP at Asp664. The data shows that p21-activated kinases can be impacted by cleavage at Asp664 (Nguyen).
Conclusion
The purpose of this paper is to study the role of misfolded proteins in Alzheimer’s disease. Misfolded proteins play a significant part in Alzheimer’s disease and can lead to toxicity and aggregation. When target proteins transform from α-helix to a β-sheet form, toxic proteins are formed. These proteins can transition native proteins into toxic proteins which becomes an ongoing cycle. Factors that may increase the chances of misfolding are aging, damage to mitochondrial function, and genetic factors. An accumulation of neuritic plaques is often found in Alzheimer’s disease which have a core of extracellular amyloid beta-peptide that formed from an amyloid precursor. Often associated with Alzheimer’s disease are neurofibrillary tangles which form from tau protein. When tau protein is hyperphosphorylated from aggregation of extracellular beta-amyloid it can form into paired helical filaments that become neurofibrillary tangles. These neurofibrillary tangles can cause damage and neuropsychiatric behaviors. Accumulation of Aβ can form into Aβ oligomers which can result in neuronal and synaptic dysfunction. Lastly, cleavage at Asp664 can affect p21-activated kinase which contributes to Alzheimer’s disease. Despite all the research on proteins in Alzheimer’s disease, the large build-up of amyloid and tau protein is not fully understood. There are still questions as to why these large build-ups of protein happen and how to prevent it.
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