Alzheimer’s - Hypotheses & Drug Targets

I. Introduction

The blood-brain barrier (BBB) is a physical barrier that keeps the extracellular fluid of the brain separate from the bloodstream. Its primary job is to carefully control the flow of chemicals from the blood to the brain and to prevent entry of pathogens and immune cells, preserving a steady environment for healthy neuronal activity. The BBB deteriorates in AD for a number of reasons, which may include the buildup of amyloid-beta and tau protein pathology. These aberrant protein aggregates can cause oxidative stress and inflammation, both of which can compromise the BBB's integrity. Increased permeability brought on by this defective barrier may allow the passage of dangerous chemicals, pathogens and immune cells into the brain. As a result, neuroinflammation and neuronal damage may worsen, advancing the pathology of AD and cognitive loss. The connection between the BBB and AD emphasizes how crucial it is to comprehend the malfunction of the barrier and maybe target it in order to create novel therapeutic methods for treating the condition.

II. AD - The Top Neurodegenerative Disorder

Symptom’s

AD is a progressive and irreversible neurological disorder that affects the brain, primarily causing problems with memory, thinking, and behavior. It is the most common cause of over 55 million cases of dementia in older adults worldwide, with 10 million new dementia patients per year. (WHO, 2023) While the exact cause of Alzheimer's is not fully understood, it is believed to be a complex interplay of genetic, environmental, and lifestyle factors.

Early symptoms may include mild forgetfulness and difficulty recalling recent events or names. As the disease advances, individuals may experience confusion, disorientation, and difficulty with problem-solving and language. They may struggle to complete familiar tasks, misplace items, and experience changes in mood or personality. As Alzheimer's progresses, individuals may have difficulty recognizing family and friends, exhibit significant memory loss, and require assistance with daily activities. Ultimately, the disease leads to severe cognitive impairment, loss of independence, and challenges with basic bodily functions, making it one of the most common causes of dementia in older adults. (Mayo Clinic, 2023)

Possible Causes And Disease Targets

AD is a complex and multifactorial neurodegenerative disorder, and its exact cause remains unclear. Several hypotheses have been proposed by researchers to explain the origins and contributing factors of AD. Here is a summary of some major alternative hypotheses:

Amyloid Hypothesis: The amyloid hypothesis is one of the most well-known theories regarding AD. It suggests that the accumulation of amyloid-beta protein in the brain, leading to the formation of amyloid plaques, is a central cause of the disease. According to this hypothesis, the aggregation of amyloid-beta disrupts brain cell function and leads to neurotoxicity, ultimately contributing to cognitive decline. (Zhang, 2023)

Tau Hypothesis: Another prominent theory focuses on the role of tau protein. In AD, tau protein forms abnormal tangles inside neurons, disrupting the cell's structure and function. The tau hypothesis suggests that these tangles play a crucial role in neurodegeneration and cognitive decline. (Zhou, 2013)

Cholinergic Hypothesis: This hypothesis posits that AD is associated with a significant decrease in cholinergic neurotransmission. The cholinergic system is responsible for producing and releasing the neurotransmitter acetylcholine, which is crucial for memory and cognitive functions. The cholinergic hypothesis suggests that the degeneration of cholinergic neurons contributes to memory deficits in Alzheimer's patients. (Vrabec, 2023)

Oxidative Stress and Inflammation: Some researchers propose that oxidative stress and chronic inflammation in the brain may contribute to AD. Oxidative stress refers to an imbalance between the production of reactive oxygen species and the body's ability to neutralize them. This imbalance can damage cells, including neurons. Chronic inflammation in the brain may also contribute to neurodegeneration. (Sharkus, 2023)

Vascular Hypothesis: New evidence from animal and clinical studies suggests that reduced blood flow due to capillary loss and endothelial dysfunction are early and primary events in AD pathogenesis, which may precede amyloid and tau aggregation and contribute to neuronal degeneration. Alzheimer disease (AD) models are based on the idea that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset. Recent evidence from clinical research indicates that endothelial dysfunction is closely related to cognitive outcomes in AD, and that therapeutic approaches that support endothelium restoration in early AD may provide a potential opportunity to stop or delay the progression of the illness. (Tarawneh, 2023)

Blood-Brain Barrier Dysfunction: Some researchers propose that defects in the blood-brain barrier (BBB) may contribute to AD. A compromised BBB could lead to increased permeability and the entry of harmful substances into the brain, contributing to neuroinflammation and neurodegeneration. (Petrushanko, 2023)

Apolipoprotein E (APOE) Gene: The APOE gene is associated with the production of a protein that plays a role in lipid metabolism and cholesterol transport. Certain variants of the APOE gene, such as APOE ε4, are considered genetic risk factors for late-onset AD. The presence of the APOE ε4 allele may influence amyloid-beta accumulation and clearance, contributing to disease development. (Zhang Lan, 2023)

It's important to note that these hypotheses are not mutually exclusive, and AD likely involves a combination of these factors. Ongoing research aims to unravel the complex interplay of these hypotheses to better understand and develop effective treatments for AD.

Alzheimer’s aka Type 3 Diabetes

AD is increasingly being recognized as a metabolic disease in addition to its well-known neurodegenerative characteristics. While it is primarily characterized by the accumulation of abnormal proteins, such as amyloid-beta and tau, leading to neurodegeneration and cognitive decline, research has revealed significant metabolic dysregulation in the brains of individuals with Alzheimer's.

The expression of the genes for insulin, IGF-I, and IGF-II as well as the insulin and IGF-I receptors is noticeably reduced in the CNS, which raises the possibility that AD is a neuro-endocrine condition that resembles diabetes mellitus but differs from it. In order to reflect this observation the term "Type 3 Diabetes" was proposed. (Steen, 2005)

Metabolism refers to the chemical processes that occur within cells to convert nutrients into energy and molecules needed for various cellular functions. In AD as in diabetes, there are several metabolic changes that contribute to the disease progression:

Reduced Glucose Metabolism: The brain's primary source of energy is glucose, which is essential for maintaining normal brain function. In Alzheimer's, there is evidence of impaired glucose metabolism in the brain. Reduced glucose utilization has been observed in specific brain regions affected by the disease, even in its early stages. (Zilberter, 2017)

Insulin Resistance: Insulin is a hormone that regulates glucose uptake and utilization in cells, including brain cells. In Alzheimer's, there is evidence of insulin resistance in the brain, similar to what occurs in type 2 diabetes. This insulin resistance may further impair glucose utilization and contribute to neurodegeneration. (Sun, 2023)

Lipid Metabolism: Lipids (fats) are vital for maintaining cell structure and function. In AD, lipid metabolism is dysregulated, leading to abnormal lipid accumulation in the brain, which can contribute to the formation of amyloid plaques. (Hu, 2023)

Mitochondrial Dysfunction: Mitochondria are cellular structures responsible for energy production. In Alzheimer's, there is evidence of mitochondrial dysfunction, which can lead to reduced energy production and increased oxidative stress, contributing to neuronal damage. (Sultana, 2023)

Dysregulated Autophagy: Autophagy is a cellular process that helps remove damaged or unnecessary cellular components. In Alzheimer's, autophagy is impaired, leading to the accumulation of toxic protein aggregates. (Li, 2023)

The emerging understanding of AD as a metabolic disorder has led to new research directions exploring how metabolic changes contribute to disease pathology and progression. Targeting metabolic pathways in the brain is becoming an area of interest in developing potential therapies for AD. As our understanding of the disease continues to evolve, addressing metabolic dysregulation may offer new avenues for therapeutic intervention in the future.

III. The Blood Brain Barrier

The blood-brain barrier (BBB) is a highly specialized and protective barrier that separates the bloodstream from the brain and central nervous system (CNS). It is formed by a layer of endothelial cells lining the blood vessels in the brain (BECs), which are tightly sealed together by specialized junctions known as tight junctions. In addition, the BBB is enriched in Glucose Transporter 1 (GLUT1), P-Glycoprotein (P-gp, aka MDR1), Glutathione S-Transferases (GSTs), and Caveolin-1. (Vulturar, 2022) (Chai, 2022) (Smeyne, 2013) (Wang, 2018)

The primary function of the blood-brain barrier is to regulate and control the movement of substances including drugs between the blood and the brain. It acts as a selective filter, allowing essential nutrients, oxygen, and certain molecules to pass from the blood into the brain while preventing harmful substances, toxins, and large molecules from entering the brain tissue. (Cleveland, 2023) Drugs designed to treat neurodegenerative diseases such as Alzheimer’s must be able to cross the BBB.

The concept of the BBB arose out of studies where chemical labels were injected into the bloodstream, highlighting the organs of the body as they diffused out, however, the tracers could not penetrate into the brain. This revealed that the BBB is extensive and covers the entire central nervous system, including the brain and spinal cord. It is not restricted to a specific location but is present throughout the brain's capillaries. The BBB is the same as the rest of the body's vasculature, except that it is more tightly regulated. (Villabona-Rueda, 2019)

The macrostructure of the BBB is formed by specialized BECs that line the capillaries' walls in the brain. These endothelial cells are tightly packed together, and their tight junctions prevent most substances from passing freely between them. Additionally, the endothelial cells have fewer fenestrations (small gaps) compared to other blood vessels in the body, further limiting the movement of molecules. (Villabona-Rueda, 2019)

The tight junctions between endothelial cells create a physical barrier that restricts the passage of most substances, including ions and large molecules. Additionally, the BBB contains specific transporters such as GLUT-1, MDR1, GSTs and others that actively pump certain molecules in and out of the brain, further regulating the passage of substances.

The blood-brain barrier is crucial for maintaining the stable and controlled environment necessary for proper brain function. It protects the brain from infections, toxins, and fluctuations in the bloodstream that could potentially harm the delicate neural tissue. However, it can also present challenges in drug delivery to the brain, as it restricts the entry of many therapeutic agents. (Achar, 2021)

The BBB is a dynamic and complex structure, and its integrity can be influenced by various factors, including inflammation and certain diseases. Understanding the blood-brain barrier and its functions is vital in medical research and drug development, as it plays a significant role in the treatment of brain-related disorders and diseases such as Alzheimer’s.

IV. Alzheimer’s Drugs