To what extent is prion aggregation responsible for Alzheimer's disease?
To What extend is prion aggregation responsible for Alzheimers's disease?

Until recently, there was no 'hard evidence' implicating an infectious, self-propagating protein or prion (proteinaceous infectious particle) in Alzheimer's disease, or any convincing evidence that  a prion-like mechanism  is involved in this disease. 

However, I quote from a recent review (Alzheimer’s and Parkinson’s diseases:  The prion concept in relation to assembled A$\beta$, tau, and alpha-synuclein) by a leading researcher in the Alzheimer's field:


  Transcellular propagation of protein pathogens, reminiscent of the spread of viruses, represents an unprecedented concept of disease. It is now known to extend beyond CJD [Creutzfeldt-Jakob disease], to include AD [Alzheimer's disease]  and PD [Parkinson's disease], which are the most common neurodegenerative diseases.


Pruisner, 
 who 
 received a Nobel prize 
 for his work on prions ('a new biological principle of infection'), was one of the first to suggest that neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, like Creutzfeldt-Jakob disease (CJD), may be due to a prion, or to a prion-like mechanism. He points out that over 80% of these diseases are sporadic, late-onset, and involve proteins present since birth (see 
 A Unifying Role for Prions in Neurodegenerative Diseases
 ).  

However, there  is one caveat.  The prion causing CJD, scrapie and kuri may be transmitted from one individual to another, and there is no evidence that Alzheimer's disease or Parkinson's disease may be so transmitted or  are in any way infectious.  

What is Alzheimer's disease?

Alzheimer's disease is a neurodegenerative disease, and a disease of ageing, that causes severe dementia worsening over time. It affects 10% of those over 65 years of age, and 50% of those aged over 85  years. There is no known cause, and no known cure.  It is the leading cause of dementia, ahead of Parkinson's disease.  Most cases of AD are sporadic, but a small percentage have a genetic origin (familial AD). 

The disease was first described (On certain peculiar diseases of old age)  by Alois Alzheimer in 1906. After histochemical analysis, Alzheimer described  two characteristic abnormalities in the postmortem brain of a 51-year old woman :  the (extracellular) neuritic plaques and the (intracellular) neurofibrillary tangles. 

There is a very nice picture of both neuritic plaques and neurofibrillary tangles in Fig 1(A) of Goedert (2005).  For a great summary of the history of AD and references to the above summary, see  A Century of Alzheimer's Disease (2006) by Goedert &amp; Spillantini.

What are the neuritic plaques?

Neuritic plaques are extracellular structures primarily composed of  a small peptide of (usually) either 40 or 42  amino acids known as  the amyloid-$\beta$ ($\beta$A), where the '$\beta$' refers to their tendency to form beta sheets.  

This small peptide arises by proteolysis of a much larger protein of unknown function, the amyloid precursor protein (APP). The APP is a trans-membrane protein with  a single membrane-spanning segment, where the N-terminus (28 amino acids) is extracellular. Two proteases are responsible for generating $\beta$A :   $\beta$-secretase and $\gamma$-secretase 

Peptide bond cleavage by   $\gamma$-secretase  occurs within the membrane-spanning region of APP and components of this proteolytic complex (the presenilins) are 'major players' in the Alzheimer's story. 

It is thought that A$\beta$ is a 'normal' brain peptide, that is it does not arise from 'aberrant' proteolysis, but its function is unknown (Goedert &amp; Spillantini, 2006). 

Finally, mutations in the APP gene are known to cause familial AD, but account for only a minority of cases. (Goedert &amp; Spillantini, 2006). 

So, the structure of the neuritic plaques is known. They consist of a small peptide of unknown function derived from a much larger trans-membrane protein of unknown function. 

And the neurofibrillary tangles?

Under the electron microscope, neurofibrillary tangles have a ribbon-like appearance called paired helical filaments.  It is now known that these structures are composed of a single protein, microtubule-associated protein Tau, or Tau protein  in an aggregated and hyper-phosphorylated state. There is  a very nice picture (electron micrograph) of a paired helical filament in  Fig 1(B) of Goedert (2005) 

What is Tau Protein?

Tau is a 'normal' brain protein characterized by Kirschner and colleagues (see here and here)  as a microbutule-binding protein, long before its role in Alzheimer's disease was realized.  

In humans, it consists of six isoforms generated by differential mRNA splicing of the transcript from a single gene, and 'imperfect repeats' within the amino-acid sequence are thought to be responsible for microtubule binding. 

Mutations in the Tau gene are not known to cause Alzheimer's disease, but are responsible for very rare neurogenerative diseases (taupathies ) such as frontotemporal dementia  (FTD) (Goedert, 2005) 

In the 'native' state Tau is phosphorylated, and is considered an intrinsically unstructured protein, (there is no crystal structure available), and it is now accepted that  'hyper-phosphorylated' Tau is the major structural component of the paired helical filament of Alzheimer's disease. 

I simply seek clarification as to whether the onset of Alzheimer's disease could have a direct correlation with an aggregate of misfolded proteins

This is where things get interesting.  There is no doubt that aggregated proteins are involved in AD. The case of Tau and $\beta$A attest to that, and the paired helical filament could be considered a misfolded state.  Can either of these proteins act  as a prion and transmit the misfolded state?  That is, can Alzheimer's disease be considered a prion disease, where a 'rogue' form of a protein transmits its 'rogueness' to 'normal' proteins? 

In the case  of Tau, it has been shown that extracellular Tau aggregates can "transmit a misfolded state from  the outside to the inside of a cell, similar to prions" by inducing fibrillization  of intracellular Tau .  In addition, aggregated intracellular  Tau can transfer to other cells. (Propagation of Tau Misfolding from the Outside to the Inside  of a Cell)

Testing of the hypothesis that prions or a prion-like mechanism is the cause of AD is a very active field and much more detail and discussion will be found in Goedert (2005).  

What are the other 'players' in the Azheimer's story?

There are many 'players' in the modern understanding of AD.  Two further important ones are the presenilins and  apolipoprotein E  (APOE).  

What are the presenilins?

Presenilins are part of the $\gamma$-secretase complex, a protease that cleaves trans-membrane proteins including APP. Mutations in the presenilin-1 gene are the  most common cause of familial AD; presenilin-2 mutations also known to cause AD. (See  Goedert &amp; Spillantini, 2006). 

And apolipoprotien E4?

A risk factor for sporadic AD is inheritance of the  ${\epsilon}_4$ allele of apolipoprotein E (APOE), a protein of fat metabolism,  but the molecular basis for this is a complete mystery.   (Goedert &amp; Spillantini, 2006, Goedert, 2005). Inheriting a single copy of the APO-$\epsilon_4$ gene more than doubles the  likelihood of developing AD; inheriting two copies increases the risk by 12-fold (see Smith, Dana, 2018)

In what looks like a major advance, gene editing has been used to convert a  APO-$\epsilon_4$  phenotype to one resembling 'normal'  APO-$\epsilon_3$.  For a great recent article, see Scientists Fix Genetic Risk Factor for Alzheimer’s Disease in Human Brain Cells by  Dana Smith (2018).