Gamma-secretase is essential in regulating intracellular signaling pathways, cell differentiation, membrane protein metabolism, and potentially even autophagy. Issues with this complex, especially in the process of 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 prior 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 can be seen 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 release 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 fragment of the B-cell maturation antigen could facilitate activated B-cell survival. 

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

The most popular theory behind the neuropathology of familial Alzheimer’s disease is the amyloid cascade hypothesis. This hypothesis states that beta-secretase first cleaves the amyloid precursor protein. Then 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. The majority 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. In 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, along with intracellular neurofibrillary tangles of tau protein, can damage DNA and RNA in neural cells.[6][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 less amyloid-beta 40. Increased levels of insoluble amyloid-beta 42 have also been seen in postmortem studies in those affected by presenilin 1 and 2 mutations when compared to those with sporadic Alzheimer’s disease. This altered production leads to an increase in the ratio of amyloid-beta 42 to 40 ratio increasing the possibility of the toxic amyloid-beta aggregation.[6][9]

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’s disease, with no known familial link. While rare, with less than 1% of Alzheimer’s 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 people with these mutations go on to develop Alzheimer disease before the age of 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 that of familial Alzheimer disease.[7][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 been noted to have the youngest onset between the ages of 30 to 50 years, and there have been several cases associated with spastic paraparesis, extrapyramidal symptoms, and cerebellar signs. Even rarer are presenilin-2 mutations that have been 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 hydrophobic core of the protein and therefore disrupting wild-type gamma-secretase activity.  

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