Table 1.
Additional molecular interactions included in the brain physiology model (detailed references are given in Table S6)
| Models being connected | Description of the interaction | References |
|---|---|---|
| 1. Connecting APP processing and sphingolipid metabolism models | Increasing Aβ levels increases SMase activity (increasing ceramide levels) | Tanabe (2013)38, Geekiyanage (2011)39, Grimm (2005)40 |
| Increasing ceramide increases BACE‐1 activity | Puglielli (2003)41 | |
| S1P modulates BACE‐1 | Jesko (2014)42 | |
| S1P inhibits APP secretion | Jesko (2014)42 | |
| Increasing SM decreases α‐secretase activity | Grimm (2005)40 | |
| Increasing AICD downregulates SPT expression | Grimm (2011)43 | |
| Aβ downregulates SphK | Gassowska (2014)44 | |
| S1P blocks SMase activity | Malaplate‐Armand (2006)45 | |
| 2. Connecting APP processing and cholesterol metabolism models | Increasing 27‐OHC levels, increases BACE‐1 activity | Dias (2014)46, Marwarha (2010)47, Marwarha (2013)48, Prasanthi (2009)31, Prasanthi (2015)49, Famer (2007)50 |
| Increasing brain cholesterol increases BACE‐1 activity | Prasanthi (2009)31, Xiong (2008)30 Grimm (2008)51, von Arnim (2008)52, Zhu (2011)53, Malnar (2012)54, Thirumangalakudi (2008)55, Cui (2011)56 | |
| Increasing 24‐OHC levels increases α‐secretase activity | Prasanthi (2009)31, Famer (2007)50 | |
| Increasing brain cholesterol increases γ‐secretase activity | Xiong (2008)30 | |
| Reducing intracellular cholesterol increases APP processing (through α‐secretase) | Cole (2005)57, Fewlass (2004)58 | |
| Increasing 27‐OHC levels decreases LRP1 levels | Marwarha (2010)47, Prasanthi (2009)31 | |
| Increasing Aβ levels decreases de novo synthesis of cholesterol (inhibiting HMGCR activity) | Grimm (2005)40 | |
| Increasing brain 27‐OHC decreases Aβ degradation | Sharman (2013)59 | |
| Increasing AICD inhibits LRP1 | Liu (2007)60 | |
| 3. Connecting sphingolipid metabolism and cholesterol metabolism models | Increasing 24‐OHC levels increases ABC transporter expression | Prasanthi (2009)31 |
| ABC transporter expression increases SM synthesis | Davis (2014)61 | |
| ABC transporter expression increases ceramide production | Davis (2014)61 | |
| Increasing 27‐OHC increases SMase activity | Dias (2014)46 | |
| Ceramide inhibits HMGCR activity (cholesterol synthesis) | Subbaiah (2008)62 |
Aβ, amyloid beta; AICD, APP intracellular domain; APP, amyloid precursor protein; HMGCR, HMG‐CoA reductase (3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase); LRP1, Low density lipoprotein receptor‐related protein 1; OHC, hydroxycholesterol; S1P, sphingosine‐1‐phosphate; SM, Sphingomyelin; SphK, Sphingosine kinase; SPT, Serine palmitoyltransferase.