Chapter 1 Part 3 How are Neurofibertangles formed in the brain ?

How are NFTs formed in the brain?

NFTs are insoluble tangles of soluble phosphoproteins called tau.  Because these tangles start forming inside neurons they are called neurofibrillary tangles or NFTs. The appearance in the brain of these NFTs as “tombstones” or “ghosts” is one of the hallmarks of AD. NFT formation requires two things:

·         An above normal amount of phosphoryl groups (PO₃^2-) coated on the tau proteins. This phosphoryl coated tau protein is called hyper-phosphorylated tau.

·         Metal ions that facilitate the formation and pairing of hyper-phosphorylated tau to form paired helical filaments (PHFt) called NFTs. 

Lesions in the brain caused by NFTs are better correlated with cognitive decline in AD than intracellular Aβ oligomer and extracellular Aβ plaque formation¹⁹.  

Does aluminum cause NFTs or does aluminum complex with NFTs after they form?

Some metal cations inhibit numerous key enzymes in the brain.  One of these key enzymes is PP2A that keeps tau from being covered with too many phosphoryl (PO₃^2-) groups (i.e. over-phosphorylated).  When PP2A is inhibited by zinc²⁰, mercury²¹, or aluminum²² ions the result is over-phosphorylation of tau leading to PHFt formation, neuronal death, and ultimately neurofibrillary tangles in place of former neurons.  Of the three cations that are known to inhibit PP2A, zinc is a neurotransmitter that is required by our brains and zinc and mercury are not on the list of suspects in the case of strange death as they are not contained in alum. Therefore Watson, zinc and mercury are “red-herrings” and this leaves aluminum in alum on the suspect list.

In 1988 aluminum chloride added to rat brain cells resulted in NFTs that were “distinct” immunochemically from human Alzheimer NFTs²³.  This resulted in more controversy but was resolved in 1998 when aluminum chloride was injected into the cerebrospinal fluid in the brains of New Zealand white rabbits²⁴.    The resulting NFTs were immunochemically identical to NFTs found in the brains of AD patients. In 1992 it was found that aluminum stimulates the interaction between filaments of hyper-phosphorylated tau. This interaction results in paired helical filaments of tau (PHFt) and NFT formation²⁵. 

Is aluminum linked to NFTs in neurons?

In 1973 levels of aluminum were found to be higher than normal in some regions of the brains of Alzheimer patients²⁶. This finding remained controversial until 1980 when a combination scanning electron microscope and x-ray spectrometer analysis showed there was aluminum in neurons with NFTs in the brains of both Alzheimer and elderly non-Alzheimer patients and no aluminum in adjacent neurons without NFTs²⁷.  Since NFTs are a hallmark of AD, this finding was the first to link aluminum to AD at the neuronal level.  Even more disturbing was the fact that aluminum and NFTs are in the neurons of the elderly in general not just those with an AD diagnosis.  These findings are consistent with research that finds aluminum in the brains of the elderly in general^28,29. 

Aluminum is a non-essential cation in our brains and an unwanted intruder.  It is obvious Watson, since aluminum promotes the formation of paired helical filaments of tau and NFTs, NFTs are at best only a secondary cause or symptom and not the primary cause of Alzheimer’s.

But Watson was looking skeptical and asked: “Since aluminum is looking more and more like the culprit in the case of strange death, why do people with the apoE4 gene have a 50% higher chance of getting AD than people without this gene?”

Holmes replied: Carriers of the apoE4 gene have lived with higher levels of Aβ peptides, oligomers, and plaque for thousands of years and not had AD.  There must be an environmental factor that facilitates the formation of Aβ peptides, oligomers, or plaque to cause AD”.    

Watson asked: “Could this environmental factor be aluminum?”

Yes Watson aluminum is a likely environmental casual factor of AD. Metal cations such as aluminum, copper, zinc, and iron are known to complex with Aβ peptides to form Aβ oligomers^16,17.  However, only aluminum complexes of Aβ oligomers are neurotoxic¹⁶.  Aluminum makes the degree of neurotoxicity worse because it has the unique property of “freezing” Aβ peptides in the oligomeric state, resulting in high concentrations of Aβ oligomers¹⁶. When these Aβ oligomers are complexed with aluminum they cause excess calcium to diffuse into neurons which can ultimately kill them.  Therefore aluminum can cause AD both with and without the apoE4 gene but is 50% more likely to cause AD in carriers of the apoE4 gene. This is due to the carriers having higher levels of Aβ peptides in their brains making it possible for aluminum to freeze more Aβ peptides in the neurotoxic oligomeric state.

Aluminum acts in five ways to increase the accumulation of Aβ oligomers in the brain putting carriers of the apoE4 gene at greater risk of getting AD:

·         Aluminum freezes Aβ peptides in the neurotoxic oligomeric state¹⁶.  

·         Aluminum lowers gene expression of neprilysin, an enzyme that is the rate limiting step in Aβ peptide and oligomer degradation^30,31.

·         Aluminum lowers gene expression of the LDL receptor LRP1, required for Aβ peptide clearance and the importation of cholesterol to neurons^30,32.

·         Aluminum increases gene expression of BACE1, the β-secretase enzyme that cleaves the amyloid precursor protein (APP) to the precursor of Aβ peptides^30,31.

·         Aluminum increases gene expression for the production of APP, the precursor of Aβ peptides³¹.

Those with the apoE4 gene are also more likely to get AD due to head trauma or aluminum accumulation leading to an ischemic event, such as stroke.  Ischemia occurs when blood flow is temporarily suspended to some regions of the brain. Sporadic AD is believed to be associated in some cases with an ischemic event³³.  Post mortem analysis of the brains of those with AD has shown that 30% have evidence of an ischemic event³³.  Shortly after an ischemic event there is increased genetic expression of an apoE protein, such as apoE4³³.  Also there is both an increased genetic expression of amyloid precursor protein (APP) and the enzyme β-secretase (BACE1) that cleaves APP to the precursor of Aβ peptides³³.  Those with the apoE4 gene have slower Aβ peptide clearance than normal.  Because of this, after an ischemic event there is even less clearance than normal in the brains of those with the apoE4 gene and more production of Aβ peptides and Aβ oligomers. 

Accumulation of aluminum in the brain increases the toxicity of Aβ oligomers, the amount of aluminum-complexed Aβ oligomers, and the likelihood of an ischemic event (see Chapter 2).   Aluminum is a likely environmental causal factor for both toxic Aβ oligomers and ischemic events and puts people with the apoE4 gene at greater risk than normal for AD.

Watson, this is the second crux of the case. Since Aβ oligomers are only a facilitating factor for AD they can be removed from our list of suspects.

Watson looked alarmed for the first time and asked:  “Is there aluminum in my brain that is ‘freezing’ neurotoxic Aβ peptides in the oligomeric state?”  Holmes replied “I am afraid that we are all suffering from some frozen neurotoxic Aβ oligomers. But luckily we can control the amount of aluminum we ingest, absorb, and excrete. As you have sensed Watson, the sum total of this research has now reached a tipping point”.

Aluminum is the only remaining suspect for causing the case of strange death.  But before we can be certain that aluminum is the culprit we need to find if aluminum has the means and motive to cause AD in the case of strange death.