Introduction

More than five million Americans have Alzheimer disease, and a subset of these cases is due to genetic disorders. This includes familial Alzheimer disease, caused by mutations in the presenilin-1 and presenilin-2 genes.[1]

Fundamentals

The presenilin proteins presenilin-1, and presenilin-2, are vital to the function of a protease complex called gamma-secretase. Gamma-secretase is a multi-subunit complex expressed in several organs and various human brain cell types. The complex cleaves several transmembrane proteins, including amyloid precursor protein. Abnormal cleavage of amyloid precursor protein has potential implications in the pathogenesis of Alzheimer disease. Researchers have also found that presenilin proteins are essential during neural cell development and migration by regulating the Notch signaling pathway.[2][3]

Molecular Level

The presenilin-1 gene is located on chromosome 14 and encodes the presenilin-1 protein. The presenilin-2 gene is located on chromosome 1 and encodes the presenilin-2 protein. Both presenilin proteins have nine helical transmembrane domains. There are two catalytic aspartyl residues; one is on the transmembrane domain 6, and one is on the transmembrane domain 7 in each protein. 

Presenilin-1 and presenilin-2 form a heterotetrameric complex with protein cofactors nicastrin, presenilin-enhancer-2, and anterior-pharynx-defective-1, creating what is called the gamma-secretase complex. The presenilin proteins form the catalytic subunit. The complex becomes destabilized and degraded if one of these components is missing. Presenilin-1 is mainly present in the Golgi, plasma membrane, and endosomes. Presenilin-2, on the other hand, is primarily found in endosomes and lysosomes.[4][5]

Function

Gamma-secretase is crucial in regulating intracellular signaling pathways, cell differentiation, membrane protein metabolism, and potentially even autophagy. Issues with this complex, especially in protein clearance in lysosomes and during autophagy, are believed to contribute to neurodegeneration.

Gamma-secretase also appears to cleave substrates to excrete them from the cell membrane. This cleavage process typically does not work with substrates with large ectodomains. After the initial shedding of a portion of the substrate's ectodomain, gamma-secretase can cleave the remaining substrate into two products. The shorter product can be secreted, and the intracellular domain remains within the cell.

An example of this process is observed in studies that have linked presenilin proteins to Notch cell-surface receptors. Notch signaling is especially vital during embryogenesis. The gamma-secretase complex is involved in the cleaving and releasing of the Notch1 intracellular domain. The Notch1 intracellular domain can then be sent to regulate transcription in the cell nucleus. While the functions of various other proteins' extracellular fragments are not yet fully understood, researchers reported that the extracellular domain of the B-cell maturation antigen could facilitate activated B-cell survival. 

Another function with potential links to the gamma-secretase complex is autophagy, when cellular material is marked for degradation and recycling via lysosome or vacuole activity. This process is fundamental in neural cells, where the loss of autophagy correlates with neurodegenerative diseases. Researchers have reported presenilin mutations in familial Alzheimer disease that impair autophagy and lysosomal activity.[5][6]

Pathophysiology

The most popular theory behind the neuropathology of familial Alzheimer disease is the amyloid cascade hypothesis. This hypothesis states that beta-secretase first cleaves the amyloid precursor protein. The amyloid precursor protein is thought to be further cleaved via the carboxypeptidase activity of gamma-secretase by cutting every three amino acids to form amyloid-beta peptides of different lengths. Most of the product produced is amyloid-beta 40, which contains 40 amino acids. The minor product is amyloid-beta 42, which contains 42 amino acids and is hydrophobic and insoluble. A situation where a mutation causes a change in the ratio of product produced, specifically an increase in amyloid-beta 42 production, can lead to amyloid-beta aggregation and deposition. This excessive amyloid-beta deposition and intracellular neurofibrillary tangles of tau protein can damage DNA and RNA in neural cells.[7][8]

Experiments with mutant presenilin-1-containing gamma-secretase complexes, as seen with familial Alzheimer disease, have suggested that the mutations can lead to an altered gamma-secretase complex. This alteration causes altered positioning of substrates for proteolysis and can lead to increased production of insoluble amyloid-beta 42 and decreased production of amyloid-beta 40. Increased levels of insoluble amyloid-beta 42 have also been seen in postmortem studies in those affected by presenilin-1 and presenilin-2 mutations compared to those with sporadic Alzheimer disease. This altered production increases the amyloid-beta 42 to 40 ratio, increasing the possibility of toxic amyloid-beta aggregation.[6][9]

Clinical Significance

Familial Alzheimer Disease

Alzheimer disease is a multifactorial disease with both genetic and environmental components. The condition causes cognitive deficits like memory impairment, language disturbance, disorientation, and even noncognitive issues like personality changes. The most common form is sporadic Alzheimer disease, with no known familial link. While rare, with less than 1% of Alzheimer disease cases, familial Alzheimer disease is believed to be caused by genetic mutations in amyloid precursor protein, presenilin-1, and presenilin-2. About half of the individuals with these mutations develop Alzheimer disease before age 60. Of note, dementia that follows an autosomal dominant inheritance pattern is autosomal-dominant Alzheimer disease. It makes up less than 1% of all Alzheimer disease cases and has a neuropathogenesis similar to familial Alzheimer disease.[9][10]

A mutation in the presenilin-1 gene is the most common cause of familial Alzheimer disease. Those affected by presenilin-1 mutations have the youngest onset between the ages of 30 to 50 years. Several cases have been associated with spastic paraparesis, extrapyramidal symptoms, and cerebellar signs. Even rarer are presenilin-2 mutations known to have a wide range of age onset. Mutations are believed to be scattered throughout the presenilin proteins, with most found close to the protein's hydrophobic core, disrupting wild-type gamma-secretase activity.  

Regarding pathology case reports, presenilin-1 mutations correlate with the presence of cotton wool plaques, ball-like plaques without dense amyloid cores. These plaques have been correlated with seizures and spastic paraparesis. Additionally, presenilin-1 mutations have been linked to more severe cerebral amyloid angiopathy than sporadic Alzheimer cases. A similarity in sporadic Alzheimer disease and presenilin 1 and 2 mutations includes the presence of Lewy body pathology in the amygdala and neocortex. Given the various phenotypes and pathological expressions within families, other genetic or epigenetic factors are likely at play.[9]