Peptides in Alzheimer's Disease

• β-Amyloid (1-42), (1-40), (1-46) and Fragments
• Amyloid (APP) Precursor 770 Fragments
• β-Amyloid (HFIP-treated) and Salts (HCI,TFA)
• β-Amyloid Mutations
• FRET-Substrates
• Labeled Amyloid Peptides
• Modified Amyloids
• Modifiers of Aβ-Aggregation
• β-and γ-Secretase Inhibitors
• Tau Fragments
• Various Products/Alzheimer's Disease

What is the Alzheimer's disease (AD)?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes and causes a complex multi-factorial disorder among the elderly (typically after the age of 65 years). It currently presents one of the biggest healthcare issues in the developed countries. First described by Alois Alzheimer in 1906, this condition predominantly affects the elderly, with increasing incidence as age advances. As the most common cause of dementia, Alzheimer's disease imposes a significant burden on patients, families, and healthcare systems worldwide.

AD manifests through a combination of genetic, environmental, and lifestyle factors. Its hallmark pathological features include the presence of extracellular amyloid-beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and widespread neuronal loss. Despite extensive research, the precise etiology of AD remains elusive, and current treatments offer only symptomatic relief without altering the disease's progression.

Although five drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment, these drugs are not capable of slowing down disease progression but only are used to relieve symptoms.

Mechanism of Alzheimer's Disease

The cause of Alzheimer's disease is poorly understood. About 70% of the risk is believed to be genetic with many genes usually involved. There are several different hypotheses trying to explain the cause of the disease, such as amyloid hypothesis, cholinergic hypothesis, tau hypothesis and mitochondrial cascade hypothesis etc. Among them amyloid hypothesis and Tau hypothesis have drawn much attention.

Amyloid Hypothesis

Aβ peptides are generated through the proteolytic cleavage of amyloid precursor protein (APP), a transmembrane protein, by enzyme complexes α, β and γ-secretases. In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposition is the basic cause of the Alzheimer disease. Specifically, this hypothesis suggests that the formation, aggregation, and deposition of Aβ peptides, and especially Aβ (1-42), is a fundamental process in AD pathogenesis which causes neurotoxicity and neurodegeneration. Based on the amyloid hypothesis, drugs that can reduce the generation of Aβ, prevent the aggregation of Aβ, and promote its clearance are thought to be promising therapeutics for AD.

Tau Hypothesis

Tau proteins are highly soluble and abundant in the neurons where they play a critical role in microtubule stabilization. In this hypothesis, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton. This may eventually causes neurodegeneration and neuronaldeath. In recent years, immunomodulation was suggested as a viable option for promoting effective clearance of Tau aggregates.

The tau protein contains 85 potential serine (S), threonine (T), and tyrosine (Y) phosphorylation sites, and under normal conditions phosphorylation helps to maintain cytoskeletal structure. Abnormal phosphorylation of tau is known to contribute to AD pathology, with approximately 45 specific phosphorylation sites identified in the AD brain. Tau is subject to multiple post-translational modifications in addition to phosphorylation, including glycosylation, oxidation and aggregation etc. Today, there is a worldwide effort under way to find better ways to treat the disease, delay its onset, and prevent it from developing.

Neuroinflammation

Neuroinflammation is a critical component of Alzheimer's disease pathology, involving the chronic activation of the brain's immune cells, primarily microglia and astrocytes. Microglia, the central nervous system's resident macrophages, become activated in response to amyloid-beta (Aβ) plaques and other pathological stimuli. Once activated, microglia release pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS). While this response initially aims to clear debris and maintain homeostasis, prolonged activation results in a detrimental cycle of inflammation, contributing to neuronal damage and synaptic dysfunction. This persistent inflammatory state exacerbates the neurodegenerative processes in Alzheimer's disease, accelerating cognitive decline and neuronal loss.

Astrocytes also play a significant role in neuroinflammation. They are another type of glial cell. In Alzheimer's disease, hypertrophy characterized and active astrocytes and upregulation of glial fibrillary acidic protein (GFAP). Cytokines and other inflammatory mediators are released by reactive astrocytes, further amplifying the inflammatory response initiated by large and small glial cells. In addition, reactive astrocytes can disrupt the blood-brain barrier (BBB), leading to increased permeability and further infiltration of peripheral immune cells into the CNS. The combined effects of activated microglia and reactive astrocytes create a toxic environment that impairs neuronal function and survival, highlighting the importance of targeting neuroinflammation as a therapeutic strategy in Alzheimer's disease research.

Other Mechanisms

In addition to the amyloid cascade and tau pathology, other mechanisms such as mitochondrial dysfunction, impaired autophagy, and altered calcium homeostasis also play roles in AD. Mitochondrial dysfunction leads to energy deficits and increased oxidative stress, while impaired autophagy hampers the clearance of misfolded proteins. Disrupted calcium homeostasis affects synaptic function and neuronal survival, further contributing to the disease.

Peptides in Alzheimer's Disease Research

Peptides in Alzheimer's disease research have broad application prospects, and provide the treatment and diagnosis of potential applications. Currently studying several types of peptides in regulating Aβ aggregation, inhibiting the tau protein phosphorylation, alleviating nerve inflammation, and enhancing the effect of nerve protection.

Amyloid-Beta (Aβ) Peptides: Aβ peptide itself is the core of AD research, both as a target and as a treatment drug. Understanding Aβ peptide structure, aggregation behavior and toxicity is very important to reduce the pathological effect of strategy.

Anti-Aβ Aggregation Peptides: The inhibition of collected Aβ peptide in preventing toxic oligomer and fiber formation shows promise. These peptides can stabilize Aβ monomer or promote the formation of non-toxic aggregation, thereby reducing the neurotoxicity induced by Aβ. For example, peptide KLVFF (Lys-Leu-Val-Phe-Phe) combined with the center of Aβ scanty water, stop the self-assembly.

Aβ-Degrading Enzymes: Using the endogenous peptides enhances Aβ degradation enzyme activity in another way. Neprilysin and insulin-degrading enzyme (IDE) are two enzymes that degrade Aβ peptides. Activating or simulating these enzyme peptides helps ease the burden of Aβ in the brain.

Tau-Targeting Peptides: Given the critical role of tau pathology in AD, peptides targeting tau aggregation and phosphorylation are being explored.

Tau Aggregation Inhibitors: Peptides that inhibit tau aggregation can prevent the formation of NFTs. For instance, the peptide Ac-VQIVYK-NH2 has been shown to block tau-tau interactions, reducing tau fibrillization.

Kinase Inhibitory Peptides: Hyperphosphorylation of tau is mediated by several kinases, including glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5). Peptides that inhibit these kinases can reduce tau phosphorylation and aggregation. An example is the peptide L803-mts, which inhibits GSK-3β activity.

Neuroprotective Peptides: Peptides with neuroprotective properties can counteract the detrimental effects of Aβ and tau pathology, promoting neuronal survival and function.

Neurotrophic Peptides: Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) support neuronal growth, differentiation, and survival. Peptides that mimic or enhance the activity of neurotrophic factors can provide neuroprotection in AD. For instance, the peptide mimetic of BDNF, LM22A-4, has shown neuroprotective effects in preclinical models.

Antioxidant Peptides: Oxidative stress is a major contributor to AD pathology. Peptides with antioxidant properties can scavenge reactive oxygen species and reduce oxidative damage. The peptide SS31, for example, targets mitochondria and protects against oxidative stress-induced neuronal damage.

Anti-Inflammatory Peptides: Targeting neuroinflammation is another strategy in AD research, with peptides being explored for their anti-inflammatory effects.

Microglia Modulating Peptides: Peptides that modulate microglial activation can reduce the chronic inflammatory response in AD. For example, the peptide NAP (davunetide) has been shown to inhibit microglial activation and reduce inflammation in AD models.

Cytokine Inhibitory Peptides: Peptides that inhibit pro-inflammatory cytokines can also mitigate neuroinflammation. The peptide COG1410, derived from apolipoprotein E, has been demonstrated to reduce inflammation and improve cognitive function in AD models.

Diagnostic Peptides: Peptides are also being developed as diagnostic tools for early detection and monitoring of AD.

Aβ Imaging Peptides: Peptides that bind specifically to Aβ plaques can be used in imaging techniques such as positron emission tomography (PET) to visualize Aβ deposition in the brain. For instance, the peptide-based radiotracer Florbetapir (18F) binds to Aβ plaques and is used in PET imaging for AD diagnosis.

Tau Imaging Peptides: Similarly, peptides targeting tau pathology can aid in imaging NFTs. The peptide-based tracer Flortaucipir (18F) is used for PET imaging of tau aggregates in AD patients.

Creative Peptides offer a versatile and promising approach in Alzheimer's disease research, encompassing therapeutic, neuroprotective, anti-inflammatory, and diagnostic applications. By targeting key pathological processes such as Aβ aggregation, tau phosphorylation, and neuroinflammation, peptides hold the potential to alter the course of AD and improve patient outcomes.

With the long-standing experience in peptide synthesis, Creative Peptides can offer the most comprehensive AD related peptides, from milligram to kilogram quantities at predefined purity levels even GMP grade peptides, for worldwide clients. Many experts working in Creative Peptides have actively pursued complicated peptide design and manufacturing for more than a decade. Consequently, our experts are skilled in complex peptide synthesis, even sophisticated peptide modifications such as glycosylation, DOTA, phosphorylation etc.

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References

1. Hardy J, Selkoe D J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics[J]. science, 2002, 297(5580): 353-356.
2. Goedert M, Spillantini M G. A century of Alzheimer's disease[J]. science, 2006, 314(5800): 777-781.
3. Selkoe D J, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years[J]. EMBO molecular medicine, 2016, 8(6): 595-608.
4. Sadala D, Ramos V, da Silva Fernandes M J, et al. Recent progresses on p-tau as a blood-based Alzheimer's disease biomarker[J]. Revista Neurociências, 2021, 29.
5. Bloom G S. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis[J]. JAMA neurology, 2014, 71(4): 505-508.
6. De Strooper B, Karran E. The cellular phase of Alzheimer's disease[J]. Cell, 2016, 164(4): 603-615.