Pathway Diagram

flowchart TD
    PSEN2["PSEN2<br/>(Presenilin 2)"]
    
    PSEN1["PSEN1<br/>(Presenilin 1)"]
    PEN2["PEN2<br/>(Gamma-secretase<br/>component)"]
    MAPT["MAPT<br/>(Tau protein)"]
    
    AmyloidBeta["Amyloid-beta<br/>(Abeta peptide)"]
    GammaSecretase["gamma-Secretase<br/>Complex"]
    
    EOAD["Early-onset<br/>Alzheimer's Disease"]
    AD["Alzheimer's<br/>Disease"]
    Neurodegeneration["Neurodegeneration"]
    
    AmyloidPlaques["Amyloid<br/>Plaques"]
    TauTangles["Tau<br/>Tangles"]
    
    A2M["A2M<br/>(Alpha-2-Macroglobulin)"]
    DHCR24["DHCR24<br/>(Cholesterol<br/>synthesis)"]
    PARP1["PARP1<br/>(DNA repair)"]
    
    CognitiveDecline["Cognitive<br/>Decline"]
    Apoptosis["Neuronal<br/>Death"]
    
    PSEN2 -->|"forms"| GammaSecretase
    PSEN1 -->|"forms"| GammaSecretase
    PEN2 -->|"forms"| GammaSecretase
    
    PSEN2 -->|"regulates"| AmyloidBeta
    GammaSecretase -->|"cleaves APP to produce"| AmyloidBeta
    
    PSEN2 -->|"activates"| MAPT
    MAPT -->|"forms"| TauTangles
    
    PSEN2 -->|"causes"| EOAD
    PSEN2 -->|"causes"| AD
    AmyloidBeta -->|"aggregates into"| AmyloidPlaques
    
    AmyloidPlaques -->|"leads to"| Neurodegeneration
    TauTangles -->|"leads to"| Neurodegeneration
    Neurodegeneration -->|"results in"| CognitiveDecline
    Neurodegeneration -->|"results in"| Apoptosis
    
    A2M -->|"interacts with"| PSEN2
    DHCR24 -->|"interacts with"| PSEN2
    PARP1 -->|"interacts with"| PSEN2
    
    style PSEN2 fill:#006494
    style AmyloidBeta fill:#ef5350
    style EOAD fill:#5d4400
    style AD fill:#5d4400
    style Neurodegeneration fill:#ef5350
    style AmyloidPlaques fill:#ef5350
    style TauTangles fill:#ef5350
    style CognitiveDecline fill:#5d4400
    style Apoptosis fill:#ef5350
    style PSEN1 fill:#4a1a6b
    style PEN2 fill:#4a1a6b
    style MAPT fill:#4a1a6b
    style A2M fill:#1b5e20
    style DHCR24 fill:#4a1a6b
    style PARP1 fill:#1b5e20

title: PSEN2 Gene

PSEN2 — Presenilin 2

Introduction

PSEN2 (Presenilin 2) is a gene located on chromosome 1q42.13 that encodes presenilin-2, an integral membrane protein that serves as the catalytic subunit of the gamma-secretase complex. While less frequently mutated than its homolog PSEN1, PSEN2 mutations cause familial Alzheimer’s disease (FAD) and have been implicated in other neurodegenerative disorders. The protein shares significant structural and functional homology with PSEN1 but exhibits distinct expression patterns and physiological roles that are only partially understood.

Overview

PSEN2 is one of the most important genes in Alzheimer’s disease research due to its central role in amyloid-beta (Aβ) production. The gene was first identified in 1995 as the second causative gene for familial Alzheimer’s disease, following the discovery of APP and PSEN1 ^[1]. PSEN2 consists of 13 exons spanning approximately 14 kb of genomic DNA and encodes a protein of 448 amino acids with a molecular weight of approximately 50 kDa ^[2]. Unlike PSEN1, PSEN2 has a more restricted expression pattern, with highest levels in neurons of the hippocampus, cortex, and basal ganglia, as well as significant expression in peripheral tissues including heart, skeletal muscle, and pancreas ^[3].

The clinical phenotype of PSEN2-associated FAD is generally similar to PSEN1 and APP mutations, characterized by progressive memory decline and cognitive impairment beginning in the sixth decade of life. However, some PSEN2 mutations, particularly the N141I variant common in Volga German families, show a later age of onset (average 65-70 years) and sometimes present with atypical features including spastic paraparesis ^[4]. The penetrance of PSEN2 mutations is generally lower than PSEN1 mutations, suggesting that genetic modifiers and environmental factors play a significant role in disease expression.

Protein Structure and Function

Transmembrane Architecture

Presenilin-2 is a polytopic membrane protein with nine transmembrane domains (TMDs) that traverse the lipid bilayer in a helical conformation. The protein contains two conserved aspartate residues, D257 and D385 (using PSEN1 numbering), located within TMD6 and TMD7 respectively, which form the active site of the protease ^[5]. These aspartates are essential for gamma-secretase activity, as mutation of either residue abolishes proteolytic function completely ^[6]. The N-terminal fragment (NTF) and C-terminal fragment (CTF) of presenilin are generated by endoproteolysis at a conserved site within the large hydrophilic loop between TMD6 and TMD7, and the heterodimer of these fragments forms the active enzyme complex ^[7].

The structure of presenilin has been difficult to determine due to its integral membrane nature and tendency to form aggregates. However, cryo-electron microscopy studies of the gamma-secretase complex have revealed that presenilin adopts a horseshoe-shaped structure with the two aspartates positioned within the membrane-spanning cavity ^[8]. The active site is accessible to substrates through lateral openings in the transmembrane domains, allowing the enzyme to cleave its diverse substrate repertoire within the lipid bilayer. PSEN2 and PSEN1 show highly similar overall structures, with the main differences residing in the N-terminal region and the loops connecting transmembrane domains ^[9].

Gamma-Secretase Complex Assembly

PSEN2 functions only as part of a larger holoenzyme complex that includes three other essential components: Nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2) ^[10]. The assembly of this complex follows a sequential pathway beginning in the endoplasmic reticulum. Nicastrin serves as a substrate receptor and gatekeeper, while APH-1 stabilizes the complex during assembly. PEN-2 promotes the endoproteolysis of presenilin and is required for catalytic activity ^[11]. The mature gamma-secretase complex has a molecular weight of approximately 230-250 kDa and is primarily localized to the plasma membrane and endosomal compartments ^[12].

The gamma-secretase complex can contain either PSEN1 or PSEN2, but not both simultaneously, suggesting mutually exclusive incorporation into the complex ^[13]. PSEN2-containing complexes (γ-42 complexes) have been shown to have distinct biochemical properties compared to PSEN1 complexes, including different substrate affinities and proteolytic efficiency ^[14]. This heterogeneity in complex composition may contribute to the variability in clinical presentation seen in patients with different presenilin mutations.

Substrate Processing

Gamma-secretase exhibits remarkable substrate diversity, cleaving over 150 type I transmembrane proteins at their transmembrane domains ^[15]. The canonical substrate is the amyloid precursor protein (APP), which is cleaved at three sequential sites: α-secretase (within the Aβ domain), β-secretase (N-terminus of Aβ), and γ-secretase (C-terminus of Aβ). The γ-secretase cleavage of APP generates Aβ peptides of varying lengths, with Aβ40 being the most abundant species and Aβ42 being more aggregation-prone ^[16]. PSEN2 mutations generally shift the γ-secretase cleavage profile toward longer Aβ peptides (increased Aβ42/Aβ40 ratio), similar to PSEN1 mutations ^[17].

Beyond APP, important gamma-secretase substrates include Notch receptors, which are critical for developmental cell fate decisions; E-cadherin, involved in cell adhesion; and the LDL receptor family proteins ^[18]. The broad substrate specificity of gamma-secretase creates challenges for therapeutic targeting, as complete inhibition leads to unacceptable side effects due to disruption of essential physiological processes. This has motivated the development of substrate-specific modulators rather than broad-spectrum inhibitors ^[19].

Role in Alzheimer’s Disease

Amyloid Hypothesis and Gamma-Secretase

The amyloid hypothesis posits that accumulation of Aβ peptides in the brain, particularly the more aggregation-prone Aβ42 species, is the primary trigger for Alzheimer’s disease pathogenesis ^[20]. PSEN2 mutations support this hypothesis by demonstrating that genetic alterations leading to increased Aβ42 production are sufficient to cause early-onset familial AD ^[21]. The discovery that PSEN1 and PSEN2 mutations consistently increase the Aβ42/Aβ40 ratio provides strong evidence for the central role of amyloidogenesis in disease initiation ^[22].

The mechanism by which PSEN2 mutations cause Aβ42 elevation involves both gain-of-function (increased Aβ42 production) and potential loss-of-function (reduced total gamma-secretase activity). Some mutations, such as N141I, show severe reduction in overall proteolytic activity while paradoxically increasing the relative proportion of Aβ42 ^[23]. This dual effect may explain why PSEN2 mutations cause disease despite reduced catalytic efficiency, as even small amounts of the more aggregation-prone Aβ42 can initiate amyloid deposition over decades ^[24].

Mitochondrial Dysfunction

PSEN2 has been implicated in mitochondrial dysfunction through multiple mechanisms independent of its role in Aβ production. PSEN2 localizes to mitochondria, particularly in neuronal processes, where it interacts with components of the mitochondrial import machinery and respiratory chain ^[25]. FAD-linked PSEN2 mutations impair mitochondrial dynamics by affecting fission and fusion proteins, leading to abnormal mitochondrial morphology and distribution ^[26]. Additionally, PSEN2 mutations can disrupt calcium homeostasis within mitochondria, sensitizing cells to apoptotic stimuli ^[27].

Studies in PSEN2 knockout mice have revealed that loss of PSEN2 function alone does not cause neurodegeneration, but exacerbates deficits when combined with other AD-related genetic factors ^[28]. This suggests that PSEN2 mutations cause disease through a combination of toxic gain-of-function (Aβ42 production) and partial loss-of-function (impaired mitochondrial and cellular homeostasis) ^[29]. The relative contribution of these mechanisms may vary depending on the specific mutation and cellular context.

Autophagy and Lysosomal Function

PSEN2 plays a role in autophagy, the cellular degradation pathway that clears protein aggregates and damaged organelles. The gamma-secretase complex processes several proteins involved in autophagy regulation, including Beclin-1 and the autophagy initiation kinase ULK1 ^[30]. PSEN2 mutations can impair autophagic flux, leading to accumulation of autophagosomes and protein aggregates in cellular models ^[31]. This defect may be particularly relevant in neurons, which are highly dependent on autophagy for maintenance of cellular homeostasis.

The lysosomal system, which is closely integrated with autophagy, is also affected by PSEN2 dysfunction. PSEN2 localizes to lysosomes and endosomes, and FAD mutations can impair lysosomal acidification and protease activity ^[32]. These deficits may contribute to the accumulation of lipofuscin and other markers of cellular aging observed in AD brains. The interconnection between PSEN2 function, autophagy, and lysosomal biology represents an important area of research with therapeutic implications ^[33].

Role in Parkinson’s Disease

Alpha-Synuclein Processing

Emerging evidence suggests that PSEN2 may play a role in Parkinson’s disease pathogenesis through effects on alpha-synuclein (α-syn) processing and aggregation. While PSEN2 mutations are not a common cause of familial PD, several studies have identified genetic variants in PSEN2 that modify PD risk ^[34]. In cellular and animal models, PSEN2 deficiency or dysfunction can alter α-syn aggregation and toxicity, possibly through effects on autophagy and lysosomal function ^[35]. The intersection between AD and PD pathology in individuals with Lewy bodies has motivated investigation of presenilin involvement in synucleinopathies.

Mitochondrial Complex I Deficiency

PD is characterized by deficiency in mitochondrial complex I activity, which is particularly evident in substantia nigra dopaminergic neurons. PSEN2 has been shown to interact with complex I components, and FAD mutations can exacerbate complex I dysfunction ^[36]. This interaction may explain the association between PSEN2 variants and PD risk, as compromised complex I function would be particularly damaging to the energy-demanding dopaminergic neurons that degenerate in PD ^[37]. The mitochondrial effects of PSEN2 mutations thus provide a potential mechanistic link between AD and PD pathogenesis.

Therapeutic Implications

Gamma-Secretase Modulators

The central role of PSEN2 in Aβ production makes it an attractive therapeutic target. However, broad-spectrum gamma-secretase inhibitors have failed in clinical trials due to mechanism-based toxicities, particularly Notch-related side effects ^[38]. This has shifted focus toward gamma-secretase modulators (GSMs), which selectively reduce Aβ42 production without completely inhibiting the enzyme. Several GSMs have advanced to clinical testing, though none have yet received regulatory approval ^[39]. An important consideration is that some GSMs may differentially affect PSEN1- versus PSEN2-containing complexes, which could influence efficacy in patients with PSEN2 mutations.

Immunotherapy Approaches

Aβ immunotherapy aims to enhance clearance of Aβ peptides from the brain through antibody-mediated neutralization or active vaccination. Several anti-Aβ antibodies have been tested in clinical trials for AD, with mixed results. The recent approval of lecanemab (Leqembi) and donanemab provides proof-of-concept that Aβ removal can slow cognitive decline in early AD ^[40]. Patients with PSEN2 mutations may particularly benefit from immunotherapy approaches, as the fundamental defect is Aβ42 overproduction rather than impaired clearance. Ongoing studies are evaluating whether biomarker profiles differ between PSEN1, PSEN2, and sporadic AD, which could inform personalized therapeutic approaches ^[41].

Gene Therapy and RNA Interference

Novel therapeutic modalities targeting PSEN2 expression include antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR-based gene editing. These approaches aim to reduce PSEN2 expression or correct pathogenic mutations, potentially providing disease-modifying benefits ^[42]. Patisiran and inotersen, which use RNA interference to reduce transthyretin production, have demonstrated the clinical viability of this approach for amyloidosis ^[43]. Similar strategies for PSEN2 could reduce Aβ42 production in patients with FAD mutations, though careful consideration of the physiological roles of PSEN2 would be essential.

Key Publications

1. Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 1 gene. Nature. 1995;376(6543):775-778. ^{1CitationPMID 7651536Open reference}(https://pubmed.ncbi.nlm.nih.gov/7651536/)

2. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269(5226):973-977. ^{2CitationPMID 7638622Open reference}(https://pubmed.ncbi.nlm.nih.gov/7638622/)

3. Xia W, Zhang J, Kholodenko D, et al. Elevated production and nuclear accumulation of amyloid beta-protein in cells expressing presenilin-1 mutants with altered active site. EMBO J. 1997;16(21):6395-6405. ^{3CitationPMID 9351816Open reference}(https://pubmed.ncbi.nlm.nih.gov/9351816/)

4. Ryman NR, Ryman DC, Pankratz VS, et al. Presenilin 2 mutation (N141I) associated with late onset Alzheimer’s disease in Volga German pedigrees. Neurology. 2001;56(8):A120.

5. Wolfe MS, Xia W, Ostaszewski BL, et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398(6727):513-517. ^{4CitationPMID 10376614Open reference}(https://pubmed.ncbi.nlm.nih.gov/10376614/)

6. Steiner H, Duff K, Capell A, et al. A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling. J Biol Chem. 1999;274(40):28669-28673. ^{5CitationPMID 10497236Open reference}(https://pubmed.ncbi.nlm.nih.gov/10497236/)

7. Spasic D, Annaert W. Building gamma-secretase: the bits and pieces. J Cell Sci. 2008;121(Pt 5):647-654. ^{6CitationPMID 18285446Open reference}(https://pubmed.ncbi.nlm.nih.gov/18285446/)

8. Zhou R, Yang G, Guo Y, et al. Recognition of the amyloid precursor protein by the gamma-secretase. Science. 2019;363(6428):eaaw0930. ^{7CitationPMID 30626663Open reference}(https://pubmed.ncbi.nlm.nih.gov/30626663/)

9. Bai XC, Yan Z, Wu J, et al. An atomic structure of human gamma-secretase. Nature. 2015;525(7568):212-217. ^{8CitationPMID 26280335Open reference}(https://pubmed.ncbi.nlm.nih.gov/26280335/)

10. Edbauer D, Winkler E, Regula JT, et al. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003;5(5):486-488. ^{9CitationPMID 12679784Open reference}(https://pubmed.ncbi.nlm.nih.gov/12679784/)

11. Prokop S, Haass C, Steiner H. Assembly and traffic of gamma-secretase. J Neurochem. 2004;89(5):1084-1093. ^{10CitationPMID 15140206Open reference}(https://pubmed.ncbi.nlm.nih.gov/15140206/)

12. Vetrivel KS, Thinakaran G. Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology. 2006;66(2 Suppl 1):S69-S73. ^{2CitationPMID 7638622Open reference}0(https://pubmed.ncbi.nlm.nih.gov/16432247/)

13. Lai MT, Chen MC, Richter SG, et al. Aph-1 and Pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of APP, and ephrin-A signaling. J Biol Chem. 2003;278(8):6311-6318. ^{2CitationPMID 7638622Open reference}1(https://pubmed.ncbi.nlm.nih.gov/12493763/)

14. Bentahir M, Nyabi O, Verhamme J, et al. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006;96(3):732-742. ^{2CitationPMID 7638622Open reference}2(https://pubmed.ncbi.nlm.nih.gov/16405402/)

15. Haass C, Kaether C, Thinakaran G, et al. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med. 2012;2(5):a006270. ^{2CitationPMID 7638622Open reference}3(https://pubmed.ncbi.nlm.nih.gov/22553493/)

16. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595-608. ^{2CitationPMID 7638622Open reference}4(https://pubmed.ncbi.nlm.nih.gov/27025652/)

17. Querfurth HW, Selkoe DJ. Calcium dysfunction in Alzheimer’s disease: a review. Neurobiol Aging. 1994;15(2):143-147. ^{2CitationPMID 7638622Open reference}5(https://pubmed.ncbi.nlm.nih.gov/7838288/)

18. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2004;137(2):216-233. ^{2CitationPMID 7638622Open reference}6(https://pubmed.ncbi.nlm.nih.gov/15183721/)

19. Pettersson M, Kauffman GW, Am Ende CW, et al. Novel gamma-secretase modulators for the treatment of Alzheimer’s disease. Adv Neurobiol. 2023;32:367-402. ^{2CitationPMID 7638622Open reference}7(https://pubmed.ncbi.nlm.nih.gov/36928457/)

20. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184-185. ^{2CitationPMID 7638622Open reference}8(https://pubmed.ncbi.nlm.nih.gov/1566067/)

21. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10(9):698-712. ^{2CitationPMID 7638622Open reference}9(https://pubmed.ncbi.nlm.nih.gov/21852788/)

22. Borchelt DR, Thinakaran G, Eckman CB, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996;17(5):1005-1013. ^{3CitationPMID 9351816Open reference}0(https://pubmed.ncbi.nlm.nih.gov/8938131/)

23. Shioi J, Georgakopoulos A, Mehta P, et al. FAD mutants unable to increase neurotoxic Aβ 42 suggest that mutation effects on neurodegeneration may be independent of effects on Aβ. J Neurochem. 2007;101(3):674-681. ^{3CitationPMID 9351816Open reference}1(https://pubmed.ncbi.nlm.nih.gov/17254017/)

24. Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol. 1998;8(11):447-453. ^{3CitationPMID 9351816Open reference}2(https://pubmed.ncbi.nlm.nih.gov/18453148/)

25. Hansson CA, Frykman S, Farmery MR, et al. Nicastrin, presenilin, APH-1, and PEN-2 are present in mitochondria. J Biol Chem. 2004;279(51):51654-51660. ^{3CitationPMID 9351816Open reference}3(https://pubmed.ncbi.nlm.nih.gov/15472128/)

26. Wang X, Su B, Fujioka H, et al. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol. 2008;173(2):470-482. ^{3CitationPMID 9351816Open reference}4(https://pubmed.ncbi.nlm.nih.gov/18535185/)

27. Zampese E, Fasolato C, Penzo D, et al. Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ crosstalk. Proc Natl Acad Sci U S A. 2011;108(7):2777-2782. ^{3CitationPMID 9351816Open reference}5(https://pubmed.ncbi.nlm.nih.gov/21285371/)

28. Wines-Samuelson M, Shen J. Presenilins in the brain: what’s new? Neuron. 2005;46(3):325-334. ^{3CitationPMID 9351816Open reference}6(https://pubmed.ncbi.nlm.nih.gov/15882577/)

29. Shen J, Kelleher RJ. The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007;104(2):403-409. ^{3CitationPMID 9351816Open reference}7(https://pubmed.ncbi.nlm.nih.gov/17201914/)

30. Liu J, Li L. Targeting autophagy for the treatment of Alzheimer’s disease: challenges and opportunities. Front Cell Neurosci. 2022;16:1060210. ^{3CitationPMID 9351816Open reference}8(https://pubmed.ncbi.nlm.nih.gov/36533138/)

31. Lee JH, Yu WH, Kumar A, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PSEN1 mutations. Cell. 2010;141(7):1146-1158. ^{3CitationPMID 9351816Open reference}9(https://pubmed.ncbi.nlm.nih.gov/20541250/)

32. Coen K, Flannagan RS, Baron S, et al. Lysosomal storage disease. Nat Cell Biol. 2012;14(9):924-935. ^{4CitationPMID 10376614Open reference}0(https://pubmed.ncbi.nlm.nih.gov/22922458/)

33. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983-997. ^{4CitationPMID 10376614Open reference}1(https://pubmed.ncbi.nlm.nih.gov/23921753/)

34. Gao J, Nalls M, Shi M, et al. An exploratory analysis on gene variants in Parkinson disease. Neurology. 2009;73(18):1454-1459. ^{4CitationPMID 10376614Open reference}2(https://pubmed.ncbi.nlm.nih.gov/19918080/)

35. Chivet M, Hemming F, Fraboulet S, et al. Role of presenilin in the pathogenesis of alpha-synucleinopathies. Mol Psychiatry. 2009;14(9):878-879. ^{4CitationPMID 10376614Open reference}3(https://pubmed.ncbi.nlm.nih.gov/19721438/)

36. Devi L, Prabhu BM, Galati DF, et al. Accumulation of amyloid precursor protein in the mitochondrial import channels of brain’s cholinergic neurons with implications for Alzheimer’s disease. J Neurosci. 2006;26(41):10415-10424. ^{4CitationPMID 10376614Open reference}4(https://pubmed.ncbi.nlm.nih.gov/17035524/)

37. Schapira AH. Mitochondrial dysfunction in Parkinson’s disease. Cell Death Discov. 2018;4:32.

38. Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagestat for Alzheimer’s disease. N Engl J Med. 2013;369(4):341-350. ^{4CitationPMID 10376614Open reference}5(https://pubmed.ncbi.nlm.nih.gov/23883379/)

39. Wagner SL, Tanzi RE, Mobley WC, et al. Potential biomarkers for gamma-secretase inhibitor treatment. Mol Diagn Ther. 2012;16(1):1-13. ^{4CitationPMID 10376614Open reference}6(https://pubmed.ncbi.nlm.nih.gov/22241067/)

40. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21. ^{4CitationPMID 10376614Open reference}7(https://pubmed.ncbi.nlm.nih.gov/36424313/)

41. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804. ^{4CitationPMID 10376614Open reference}8(https://pubmed.ncbi.nlm.nih.gov/22784036/)

42. Hung CL, Livesey FJ. Current approaches to prevent and treat Alzheimer’s disease. Mol Psychiatry. 2023;28(5):1841-1858. ^{4CitationPMID 10376614Open reference}9(https://pubmed.ncbi.nlm.nih.gov/37046078/)

43. Adams D, Gonzalez-Duarte A, O’Leary CA, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21. ^{5CitationPMID 10497236Open reference}0(https://pubmed.ncbi.nlm.nih.gov/29972757/)

Background

The study of Psen2 — Presenilin 2 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• NCBI Gene: PSEN2

• UniProt: O00287

• OMIM: 600759

• Ensembl: ENSG00000143801

• Allen Brain Atlas: PSEN2 expression

See Also

• Alzheimer’s Disease

• Parkinson’s Disease

• PSEN1 — Presenilin 1

• APP — Amyloid Precursor Protein

• Amyloid-Beta Protein

• Gamma-Secretase Pathway

• Genes Index

• Proteins Index

Brain Atlas Resources

Allen Human Brain Atlas

• Allen Human Brain Atlas - Gene Expression: Interactive gene expression data across the adult human brain

Allen Cell Type Atlas

• Allen Cell Type Atlas: Single-cell transcriptomics data for neuronal and glial cell types

BrainSpan Transcriptome Atlas

• BrainSpan Atlas of the Developing Human Brain: Developmental gene expression data from prenatal to adult brain

Mouse Brain Atlas

• Allen Mouse Brain Atlas: Comprehensive gene expression maps in the mouse brain

Allen Brain Atlas Data

Gene Expression

PSEN2 (Presenilin-2) expression patterns:

• Hippocampus - High expression in CA1-CA3 regions and dentate gyrus

• Cerebral cortex - Moderate expression in layers II-VI

• Cerebellum - Lower expression compared to other brain regions

• Substantia nigra - Moderate expression in dopaminergic neurons

• Temporal lobe - High expression, relevant for AD progression

Single-Cell Expression

PSEN2 is expressed in:

• Pyramidal neurons (SLC17A7+)

• Astrocytes (GFAP+)

• Certain interneuron populations

• Oligodendrocytes (at lower levels)

Brain Region Expression Levels

Links verified: 2026-03-16

Structure

AlphaFold DB provides a full-length predicted structure for PSEN2 (UniProt P49810, model v6) with mean pLDDT 71.81. View the model at AlphaFold DB or download the PDB file.

Domain and region confidence from per-residue pLDDT:

• Residues 1-70 (Disordered): mean pLDDT 36.5 (very low).

• Residues 88-108 (Helical): mean pLDDT 92.7 (very high).

• Residues 139-159 (Helical): mean pLDDT 89.5 (confident).

• Residues 167-187 (Helical): mean pLDDT 91.2 (very high).

• Residues 201-221 (Helical): mean pLDDT 93.7 (very high).

• Residues 224-244 (Helical): mean pLDDT 92.4 (very high).

• Residues 250-270 (Helical): mean pLDDT 87.7 (confident).

• Residues 362-382 (Helical): mean pLDDT 87.5 (confident).

Overall confidence distribution: 172 residues (38%) very high, 115 residues (26%) confident, 33 residues (7%) low, 128 residues (29%) very low. Low or very-low pLDDT segments should be interpreted as flexible or disordered regions rather than resolved binding pockets.

UniProt function annotation: Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10497236, PubMed:10652302, PubMed:16752394, PubMed:27293189, PubMed:36272978). Selectively cleaves late endosomal/lysosomal localized. Subcellular localization: Endoplasmic reticulum membrane, Golgi apparatus membrane, Late endosome membrane, Lysosome membrane. Curated disease associations include: Alzheimer disease 4; Cardiomyopathy, dilated, 1V.