Alpha secretases are a family of

proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

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 ...

(APP) in its

transmembrane region Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

. Specifically, alpha secretases cleave within the fragment that gives rise to the

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

-associated

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

amyloid beta Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...

when APP is instead processed by

beta secretase Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enco ...

and

gamma secretase Gamma secretase is a multi-subunit protease complex, itself 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. Th ...

. 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; el, Ἀδάμ, Adám; la, Adam is the name given in Genesis 1-5 to the first human. Beyond its use as the name of the first man, ''adam'' is also used in the Bible as a pronoun, individually as "a human" and in a collective sense as " ...

('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 the blo ...

and

metalloprotease A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...

domain') family, which are expressed on the surfaces of

cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

and anchored in the

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

. Several such proteins, notably

ADAM10 A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ''ADAM10'' gene. Function Members of the ADAM family are cell surface proteins with a uni ...

, 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 polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...

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. Chemical characteristics ADAM17 ...

(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 ADAM19 (A Disintegrin And Metalloproteinase 19, MADDAM, meltrin beta), is a human gene. Function This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins st ...

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 substrates 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 remembered, ...

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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...

signaling and promote

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

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 Pituitary adenylate cyclase-activating polypeptide also known as PACAP is a protein that in humans is encoded by the ''ADCYAP1'' gene. pituitary adenylate cyclase-activating polypeptide is similar to vasoactive intestinal peptide. One of its effect ...

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

transmembrane protein A transmembrane protein (TP) 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 frequentl ...

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 plat ...

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 onset ...

-complexed form. The

Notch pathway The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembr ...

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