Alzheimer’s Part II: Somatostatin and More

Previously, we briefly described the construction of our “canonical” lists of up/down-regulated transcripts in the human Alzheimer’s brain. We also mentioned somatostatin (SST) as a gene that stood out. That’s because in 35 studies examining the Alzheimer’s brain, SST was downregulated 13 times. No other transcript was up- or down-regulated that many times. Below is a look at the most altered transcripts in the two lists: 

upregulated in canonical Alzheimer's	count		downregulated in canonical Alzheimer's	count
ITPKB	12		SST	13
GFAP	11		RGS4	12
AEBP1	10		SVOP	11
APLNR	10		PCSK1	11
CD44	8		RPH3A	10
NUPR1	8		CARTPT	10
p8	8		CRYM	9
CHST6	8		STMN2	9
AQP1	7		GABRG2	9
SLC7A2	7		NRN1	9
AHNAK	7		GAD1	9
SERPINA3	7		INA	9
			VSNL1	9
			BEX5	9

If we adjust gene counts for the frequency with which they appear in brain-related studies in our database, the basic picture above does not change radically. SST falls, however, to 3^rd in importance and SVOP rises to #1. In terms of upregulated genes, ITPKB retains its position, but GFAP falls to #6.

Though our "canonical" lists are purely transcriptomic, our database does contain a few proteomic studies relating to Alzheimer's. In one recent study, Quantitative Proteomic Analysis of the Frontal Cortex in Alzheimer's Disease, somatostatin was the single most strongly downregulated protein. What's more, which of the lists within our database best intersected downregulated proteins in this study? Our "canonically downregulated in Alzheimer's list", with a -log(P) of 4! So much for the dogma that transcriptomic and proteomic results show little or no correlation.

In general, significantly downregulated transcripts outnumber significantly upregulated transcripts in the two canonical lists. 28 transcripts appear at least 8 times in the downregulation list, while only 8 transcripts appear 8 or more times in the upregulation list. This is the opposite of the case in mouse Alzheimer and EAE models, where upregulation dominates. 

Somatostatin certainly has been mentioned in the context of Alzheimer’s. In one MS study, the short (14 aa) form of SST was found to bind oligomeric amyloid plaques (Somatostatin binds to the human amyloid beta peptide and favors the formation of distinct oligomers). The authors of this paper followed up with a review summarizing the somatostatin/Alzheimer’s link (Somatostatin in Alzheimer's disease: A new Role for an Old Player). Other reviews and research papers on the subject can be found.

Given the presence of “Somatostatinopathies”, there are indeed drugs designed to compensate for low somatostatin levels in various tissues. Here’s a recent example of an SST analog altering plaque pathology in mice: Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain.

We mentioned the possible relevance of antiretroviral therapy to Alzheimer’s disease in our previous post. We’ll delve deeper into the topic later, but for now, we note that antiretrovirals (see PMID 21909266) are the only drugs in our database that specifically upregulate SST in the brain (to see for yourself, select the WhatIsMyGene “relevant studies” app, enter “sst”, choose “upregulation” under “Regulation”, and “Drug” under “Study Type”). Ignoring brain-specific studies, one can find a number of compounds that seem to upregulate SST (Vitamin D is one, at least in the colon).

Note 12/16/2020: We've stumbled across a few more drugs that may increase SST levels in the brain: propanolol-HCl and allopurinol. As we add more studies to our database, it is likely that more SST-upregulating compounds will be noted.

Note 2/21/2022: Another observation is that SST is strongly differently altered at varying time points in stem cell differentiation. For example, it's the single most strongly upregulated gene in a comparison of mouse stem cells differentiating to pancreas cells at day 15 vs day 8 (PMID 22278131). Here, SST isn't necessarily a key effector of Alzheimer's, but it is found in a swarm of genes relevant to stemness. A number of our posts focus on the relationship between Alzheimer's and stem cells/stemness.

Unlike SST, SVOP has received little mention with respect to Alzheimer’s. We don’t find any brain-specific studies wherein a drug upregulated SVOP, but we do note that hydroxyurea, a compound proposed to alleviate the effects of Alzheimer’s (Hydroxyurea attenuates oxidative, metabolic, and excitotoxic stress in rat hippocampal neurons and improves spatial memory in a mouse model of Alzheimer’s disease), upregulated SVOP in mouse embryos (PMID 27208086).

whatismygene.com 

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