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The Journey to Brain Annihilation

How It Happens: Brain Degeneration in Alzheimer’s Disease

In the depths of the human mind, a terrifying mystery lurks. It starts with a forgotten name here, and a misplaced item there. Slowly but surely, you begin to to lose your memories…

In this article, we will be discussing the journey to brain annihilation in the context of Alzheimer’s disease (AD). Bear with us, as things are about to get science-y.

Alzheimer’s Starts With Your Genes

Genes are sections of DNA that contain the set of instructions to produce one specific molecule in your body, usually a protein.

The crucial gene involved in the development of Alzheimer’s Disease is the Apolipoprotein E (apoE) gene.

ApoE is mainly responsible for:

 

    • Transporting fats in the bloodstream

    • Maintaining neuronal health and repair

    • Modulating immune responses

There are three common alleles of the apoE gene. Alleles are basically different versions of a gene. People carrying the apoE4 allele experience double or triple the chances of developing Alzhemer’s. Carrying one allele increases Alzheimer risk; having two elevates that risk further!

Substitution mutations on Chromosome-19 cause development of the apoE4 allele.

These mutations involve changes at positions 112 and 158 in the APOE gene sequence, where the amino acid, arginine (R) is replaced by cysteine (C).

Link to BDNF

Let’s link this to a super important protein in your brain called the Brain-derived Neurotrophic Factor (BDNF). It is a neurotrophin (brain growth factor) involved in growth, development and maintenance of neurons in the hippocampus and cortex

BDNF is able to:

  • Support survival of existing neurons and synapses
  • Support development and differentiation of neurons
  • Facilitate synaptic plasticity — BDNF increases the ability of neurons to modify their connections for brain network remodelling upon damage

ApoE4 and BDNF Are Enemies

Sadly, the ApoE4 allele and the BDNF are enemies. The ApoE4 allele sabotages the production of BDNF.

It does so by increasing nuclear translocation of histone deacetylases (HDACs) in human neurons, which then  reduces BDNF expression.

The apoE4 allele causes more HDACs to move from the cytoplasm to the nucleus of the neurons. HDACs remove acetyl groups from histone proteins. This restores the positive charge on the histones, making the DNA coil more tightly around the histone.

Now, it is harder for general transcription factors and RNA polymerase to access and bind to the promoter region of the BDNF gene.

Alzheimer's Association With Bad Proteins

People with Alzheimer’s Disease are associated with “bad” protein formations. Specifically,

Abnormal Tau in Alzheimer's Disease

Tau is a protein that normally stabilises the microtubules in neurons. They maintain the shape of neurons and help with transport of substances. However, with reduced BDNF, tau protein undergoes abnormal modifications.

There are enzymes called kinases and phosphatases that add phosphate groups to the tau protein, to activate it. BDNF is like the “supervisor” of these enzymes, making sure they work properly.

With reduced BDNF, the enzymes are dysregulated. This causes tau to become hyperphosphorylated and start aggregating within the neurons.

These aggregates form twisted filaments, known as paired helical filaments (PHFs) and straight filaments, which are the primary components of neurofibrillary tangles (NFTs).

The disruption caused by NFTs in the neurons hinder their ability to receive nutrients, maintain proper function, and communicate with other neurons.

Such formation of NFTs in AD patients normally begin in the transentorhinal and hippocampal region, slowly spreading to the neocortex. 

The transenhortinal region is associated with processing information related to memory and spatial navigation.

Next, the hippocampal region is associated with consolidating short-term memories into long-term memories. Lastly, the neocortex is involved in higher cognitive functions such as perception, motor control, spatial reasoning, and language.

This suggests that in AD, it starts with forgetting a simple incident that happened a few years back. Then you forget certain words and even think illogically.

Beta-amyloid in Alzheimer's Disease

Beta-amyloid is derived from Amyloid Precursor Protein (APP). APP is a protein found on the surface of neurons. It helps direct the movement of neurons during early development. It can also help neurons bind to one another.

APP undergoes processing to produce beta-amyloid peptides and generate other products with neuroprotective and neurotrophic function. There are two pathways of APP processing 1. the non-amyloidogenic pathway and 2. the amyloidogenic pathway. The amyloidogenic pathway releases the beta-amyloid 42 peptide, the most “toxic” one that is commonly seen in AD patients. It has a higher tendency to clump together. BDNF normally regulates the enzymes involved in APP processing. Reduced BDNF levels could affect this modulation, favouring the amyloidogenic pathway. The beta-amyloid 42 peptides aggregate within the synapses, forming plaques. These plaques block communication between neurons and trigger inflammatory responses in the brain. Beta-amyloid deposits in the brain start in the basal neocortex, spreading throughout the hippocampus and eventually the rest of the cortex. In AD patients, beta-amyloid plaques also tend to build up in cerebral blood vessels, likely seen in vascular dementia as well. This is why beta-amyloid plaques are not solely linked with AD, but rather associated with an overall neurodegeneration of the brain.

Inflammation In The Brain

Microglia, the immune cells of the brain, release ROS and pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-8, tumour necrosis factor-alpha (TNF-α), in response to increased beta-amyloid plaque deposits.

Lo and behold, excessive ROS an cause oxidative modifications to amino acid residues within beta-amyloid peptides, leading to changes in their structure.

These structural changes may alter the aggregation properties of beta-amyloid, potentially affecting the formation of beta-amyloid oligomers and fibrils.

IL-8 promotes the processing of amyloid precursor protein (APP) toward amyloidogenic pathways, contributing to the formation of more beta-amyloid plaques.

This ultimately leads to chronic inflammation of the microglia, causing constant production of these ROS and cytokines. It all forms a vicious cycle.

What About Dementia That Is Not Alzheimer's?

Beta-amyloid plaque build up is commonly seen in post mortem brain tissue of healthy elder individuals. Beta-amyloid plaque build up can occur almost everywhere in the brain.

As you get older, more and more beta-amyloid aggregates build up in your brain, a natural hallmark of neuro-degeneration associated with aging.

Surprisingly, NFTs can also be found in older individuals without AD. The presence of a few NFTs in healthy aging brains does not necessarily indicate the presence of a neurodegenerative disease or significant cognitive impairment.

However, the accumulation of NFTs, along with other pathological changes, can contribute to cognitive decline in some individuals as they age.

That’s because these healthy individuals have properly functioning mechanisms that help to “clear out” these bad protein build ups from their brain.

AD patients don’t.

Glymphatic System - The Hero That Drives Out The Villians

Our brains have naturally equipped themselves with mechanisms that “drive” or “clear out” the protein buildup. They lie within the glymphatic system.

The glymphatic system is a network of perivascular spaces through which cerebrospinal fluid (CSF) and interstitial fluid (SF) can move through the brain, clearing metabolic waste and protein build up like beta-amyloid and tau, from the brain tissue.

The key player in the glymphatic system that helps “drive out” the protein buildup is Aquaporin-4 (AQP4), a transmembrane protein found at the end-feet of astrocytes.

AQP4 channels located in the end-feet of astrocytes play a crucial role in the glymphatic system by facilitating the movement of CSF through the brain tissue.

Unfortunately, due to the apoE4 allele, AQP4 expression is inhibited in a manner similar to how BDNF expression is inhibited by the apoE4 allele.

Without APQ4, there is going to be continua build up of the protein waste!

Approaches To The Treatment Of Alzheimer's

The general consensus is that there is no cure for AD. However, there are a few interventions that hold some promise:

  • target the enzymes involved in pathology of beta-amyloid and tau
  • increase BDNF through gene therapy
  • Increase AQP4
  • Target the apoE gene

There isn’t a holy grail treatment for Alzheimer’s. But because of its complexity, many interventions are currently being explored that aim to target the different players involved.