Alpha secretases are a family of

proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s that cleave

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...

(APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

-associated

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

when APP is instead processed by beta secretase and

gamma secretase Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most ...

. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the

ADAM Adam is the name given in Genesis 1–5 to the first human. Adam is the first human-being aware of God, and features as such in various belief systems (including Judaism, Christianity, Gnosticism and Islam). According to Christianity, Adam ...

('a

disintegrin Disintegrins are a family of small proteins (45–84 amino acids in length) from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion. Operation Disintegrins work by countering th ...

and metalloprotease domain') family, which are expressed on the surfaces of cells and anchored in the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ''ectodomain shedding''. APP cleavage

ADAM10 consists of two

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

s, a disintegrin domain and a prodomain; however, only the prodomain is required for APP processing. Other ADAM proteins,

ADAM17 A disintegrin and metalloprotease 17 (ADAM17), also called TACE (''tumor necrosis factor-α-converting enzyme''), is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases, activated by substrate presentatio ...

(also called TACE, ''tumor necrosis factor-α converting enzyme''),Detlev Ganten, Aloys Greither : ''Molekularmedizinische Grundlagen von altersspezifischen Erkrankungen'', 2004,

Springer-Verlag Springer Science+Business Media, commonly known as Springer, is a German multinational publishing company of books, e-books and peer-reviewed journals in science, humanities, technical and medical (STM) publishing. Originally founded in 1842 in ...

ADAM9 Disintegrin and metalloproteinase domain-containing protein 9 is an enzyme that in humans is encoded by the ''ADAM9'' gene. Function This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this fami ...

, and ADAM19 have also been identified as alpha secretases; extracellular expression of mutant ADAM9 (also known as MDC9 or meltrin gamma) lacking the membrane anchor domain has been suggested as one of many possible means of Alzheimer's prevention and treatment exploiting the alpha secretase pathway. Two distinct modalities of alpha-secretase activity have been observed in cells; constitutive activity occurs mainly at the cell surface and is independent of regulatory mechanisms inside the cell, while regulated activity occurs mainly in the golgi and is dependent on the activity of

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

. Alpha-secretase activity in the golgi is thought to compete directly with the beta-secretase pathway for APP

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

s during membrane protein maturation. Cell-surface cleavage by alpha secretase is very rapid after APP reaches the cell surface. The activity of alpha secretases has been implicated in the regulation of learning and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

formation. Release of the APPsα ectodomain has

neurotrophic Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trop ...

effects that counteract apoptotic signaling and promote

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

formation, processes that are upregulated when ADAM10 is overexpressed. Alpha secretase activity has also been observed to be upregulated in response to the signaling

PACAP. Related alpha-secretases, including ADAM10, have also been implicated in similar maturation events for other

transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...

s such as

MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on ...

proteins. Recent evidence suggests that some such proteins are first processed to ectodomains by alpha secretases and subsequently cleaved by another Alzheimer's-associated protease

complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

in its

presenilin Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early ons ...

-complexed form. The Notch pathway bears many similarities to APP processing and is also regulated in part by ADAM10.

References

{{Proteases Alzheimer's disease Membrane proteins EC 3.4.24