Discussing major hypotheses of Alzheimer’s disease

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Alzheimer’s disease (AD) is a severe neurological condition. It was first proposed by the German doctor Alois Alzheimer in 1911 and was officially called Kraeplin. Memory loss, mental decline, and impaired motor balance are the most common clinical signs of Alzheimer’s disease.

As an age-related condition, the rise in the older population also drives the demand for Alzheimer’s treatment drugs. According to the World Alzheimer Report, there will be 131 million Alzheimer’s individuals worldwide by 2050.

The pathological alterations in Alzheimer’s disease are complicated and varied. Neuronal loss, synaptic problems (such as synaptic loss and protrusion plasticity deficits), extracellular amyloid-beta (βA) deposition to form amyloid plaques, and improperly phosphorylated Tau protein to produce intracellular neurofibrillary tangles are all frequent in Alzheimer’s disease.

The reasons for various pathological changes cannot be explained at present, and the pathogenesis is still unclear. There are three classic hypotheses on the pathogenesis of AD.

Aβ cascade hypothesis

In the pathogenesis of Alzheimer’s disease, the Aβ cascade hypothesis is the most popular theory. One of the key pathogenic features of AD is the accumulation of Aβ to create amyloid plaque. Secretase degradation produces Aβ from amyloid precursor protein (APP). The secretases α-secretase, β-secretase (BACE), and γ-secretase are involved in two routes for APP degradation.

In the amyloid pathway, BCAE cleaves APP to produce sAPPβ protein, which is then cleaved by γ-secretase to produce Aβ polypeptides, such as Aβ1-42, Aβ1-40, and released into the extracellular domain, where they eventually aggregate to form amyloid plaques, leading to the development of AD.

Hydrolysis pathway of APP in vivo. Image from reference

Binding to soluble, toxic aggregates of Aβ selectively to neutralize and eliminate it is thought to help alleviate neurodegenerative processes in AD. Various drugs have been developed based on this hypothesis. Aducanumab is a representative drug targeting APP, a monoclonal antibody of Biogen, and was approved on June 7^th, 2021, for marketing by the FDA.

Schematic diagram of monoclonal antibodies targeting APP. Image from reference

Furthermore, Lilly’s Donanemab and Roche’s Gantenerumab are now in clinical phase III, while Eisai and Biogen’s Lecanemab is in the FDA’s rapid application stage, based on the similar mechanism of action and target. Fierce Pharma listed the most anticipated new medication releases for 2022 on February 7^th, 2022, with Donanemab and Ganteneruma coming in first and third place.

Abnormal phosphorylation of tau protein

Another prominent pathogenic characteristic of Alzheimer’s patients is neurofibrillary tangles (NFTs). Excessive or abnormal phosphorylation of intracellular Tau protein causes it to lose its biological activity of promoting microtubule assembly, resulting in microtubule depolymerization and axonal dysfunction, which leads to neuron degeneration and nerve cell apoptosis, resulting in Alzheimer’s disease.

The abnormal phosphorylation of Tau protein is caused by the high expression of various phosphorylated kinases, such as glycogen synthase kinase 3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), and tyrosine kinase, which are considered potential drug targets for AD treatment.

Abnormal phosphorylation of Tau protein. Image from reference

Cholinergic hypothesis

The cholinergic theory was the first to describe the pathophysiology of Alzheimer’s disease.

In Alzheimer’s patients, Doucette et al. discovered a significant loss of basal forebrain cholinergic neurons, which resulted in decreased acetylcholine transferase (ChAT) operation for acetylcholine synthesis and serious depletion of presynaptic cholinergic transmitters, resulting in cognitive function decline.

The cholinergic hypothesis proposes that the fall in cholinergic levels is due to decreasing activity of Cholinesterase, which includes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ChAT.

The FDA has authorized many Cholinesterase inhibitors for the treatment of AD, including donepezil hydrochloride and memantine hydrochloride/donepezil hydrochloride. They are still used as first-line therapeutic drugs to treat mild to moderate Alzheimer’s disease.

Even though these drugs play a significant role in postponing the onset of AD, their limited effects prevent them from effectively treating the disease.

Summary

In addition to the three hypotheses of the Aβ cascade, other reasons for the pathogenesis of AD include aberrant phosphorylation of Tau protein and cholinergic, neuroinflammation, inappropriate excitation of the glutamate system, mitochondrial dysfunction, and others. The pathophysiology of Alzheimer’s disease is currently being researched by scientists.

Only aducanumab has been introduced to the market in nearly 20 years. More drugs and therapies to improve the condition are urgently needed as the global aging issue becomes more serious.

To aid with the development of AD treatment medications, ACROBiosystems has created Tau protein (TAU-441), amyloid precursor protein (APP), and β-secretase-1 (BACE1).

Product list

Source: ACROBiosystems

Verification data

TAU-441 (Met 1 - Leu 441)

Human Tau-441 / 2N4R Protein, His Tag Human Tau-441, His Tag (Cat. No. TAU-H51H3) on SDS-PAGE under reducing (R) condition. The gel was stained overnight with Coomassie Blue. The purity of the protein is greater than 90%. Image Credit: ACROBiosystems

TAU-441 (Gly 273 - Glu 380)

The purity of Human Tau-441 (273-380), His Tag (Cat. No. TAU-H51H5) is greater than 95% verified by SDS-PAGE and more than 90% verified by SEC-MALS. Image Credit: ACROBiosystems

TAU-441 (Ser 241 - Glu 380)

The purity of Human Tau-441 (241-380), His Tag (Cat. No. TAU-H51H4) is greater than 95% verified by SDS-PAGE and more than 90% verified by SEC-MALS. Image Credit: ACROBiosystems

APP

The purity of Human Amyloid Precursor, His Tag (Cat. No. AMR-H52H4) is greater than 95% verified by SDS-PAGE and more than 85% verified by SEC-MALS. Image Credit: ACROBiosystems

BACE1

The purity of Human BACE-1, His Tag (Cat. No. BA1-H5220) is greater than 95% verified by SDS-PAGE and more than 95% verified by SEC-MALS. Image Credit: ACROBiosystems

References

1. Ju Y, Tam KY. Pathological mechanisms and therapeutic strategies for Alzheimer’s disease. Neural Regen Res. 2022 Mar;17(3):543-549. doi: 10.4103/1673-5374.320970.
2. Zhang X, Song W. The role of APP and BACE1 trafficking in APP processing and amyloid-β generation. Alzheimer’s Res Ther. 2013 Oct 8;5(5):46. doi: 10.1186/alzrt211.
3. Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci. 2004 Nov 15;117(Pt 24):5721-9. doi: 10.1242/jcs.01558.

About ACROBiosystems

ACROBiosystems is a leading manufacturer of recombinant proteins and other critical reagents to support the development of target therapeutics. The company employs an application-oriented development strategy, with a particular focus on product design, quality control, and solution-based support. Our products and services enable anyone in the field of drug development to have a more intuitive and streamlined process.

To respond to the coronavirus pandemic, ACROBiosystems has developed SARS-CoV-2 antigens specifically designed and optimized for serological test kits, including Spike-derived antigen S1, RBD, and Nucleocapsid protein. Proteins have been supplied to diagnostic companies in large quantities.

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