**4. Presenilin biological functions**

Presenilins are aspartyl proteases and constitute a subunit of γ-secretase complex involved in the processing of APP and producing various Aβ peptides (*described in Section 5*). Besides that, presenilins are involved in numerous biological processes, playing various molecular functions in distinct subcellular compartments. Presenilins reprocess more than 90 substrates [30]. Presenilin substrates are involved in various signalling pathways, and several examples are provided in subsequent text.

Receptor tyrosine-protein kinase erbB-4 (ErbB4) processing by presenilins leads to enhanced spine formation through activation of Rac signalling [31]. Furthermore, presenilin-dependent cleavage of ErbB4 interplay is crucial for signal transduction during cells maturation [32]. Importantly, ErbB4 is involved in EGF/neuregulin signalling crucial for cell proliferation, differentiation, apoptosis, oligodendrocyte maturation, angiogenesis, synapse formation, LTP, and nerves myelination [33]. Another presenilin substrate of great biological importance is E-cadherin, which misprocessing affects transcriptionally regulated genes downstream of E-cadherin, involved in cell adhesion [34]. Next to that, glutamate receptor proteolysis performed by γ-secretase complex was found to be crucial for synaptic transmission [35]. Furthermore, VEGF receptor proteolysis and phosphorylation controlled by presenilins were reported to be important for angiogenesis, what could have further consequences in damages of brain areas by interfering with oxygen and energy supply [36]. Presenilin substrates selection is also a way of modulation of cell signalling and processing of presenilins' substrates regulated by the γ-secretase substrate-recruiting factors (γSSRFs) [37]. This establishes a complex signalling network of the process important in brain, thus in PA and AD.

in transmembrane domains (TMDs). PS1 and PS2 comprise nine TM, among them TM1-6 are located at N′-terminal and TM7-9 at the C′-terminal. The catalytic centre with aspartate residues is located at the cytoplasmic side of TM6 and TM7, forming large hydrophilic loop (HL) [14]. Presenilins are activated by endoproteolysis yielding N′-terminal and C′-terminal portions. Endoproteolytical cleavage of PS1 occurs at HL, with the predominant cleavage site between amino acids 291 and 292, generating 28 kDa N′-terminal and 17 kDa C′-terminal fragments [23]. Similarly, PS2 is endoproteolytically cleaved into 35 kDa N′-terminal and 20 kDa C′-terminal fragment [24]. The most common mutations of presenilins occur in gene portion encoding C′-terminal, containing proline, alanine and leucin residues, and are usually loss of function for presenilins [25]. Due to protein structure complexity, presenilins interact with

Presenilins are ubiquitously expressed, with some tissue-specific differences. Generally, *PSEN1* transcript is expressed at higher levels than *PSEN2*. The expression pattern of *PSEN1* and *PSEN2* in the brain is similar and present in different brain cells, such as cortical neurons, hippocampal neurons, granule cells or neurons of amygdala [26], and different types of glial cells [27]. In neurons, presenilins are expressed in the cell body and dendrites [28] and are localized in several subcellular compartments, that is, rough endoplasmic reticulum, Golgi complex, mitochondria, and at plasma membrane [29]. Moreover, presenilins were found to be expressed in several non-nervous cells and tissues, including lymphoblasts, fibroblasts,

Presenilins are aspartyl proteases and constitute a subunit of γ-secretase complex involved in the processing of APP and producing various Aβ peptides (*described in Section 5*). Besides that, presenilins are involved in numerous biological processes, playing various molecular functions in distinct subcellular compartments. Presenilins reprocess more than 90 substrates [30]. Presenilin substrates are involved in various signalling pathways, and several examples are

Receptor tyrosine-protein kinase erbB-4 (ErbB4) processing by presenilins leads to enhanced spine formation through activation of Rac signalling [31]. Furthermore, presenilin-dependent cleavage of ErbB4 interplay is crucial for signal transduction during cells maturation [32]. Importantly, ErbB4 is involved in EGF/neuregulin signalling crucial for cell proliferation, differentiation, apoptosis, oligodendrocyte maturation, angiogenesis, synapse formation, LTP, and nerves myelination [33]. Another presenilin substrate of great biological importance is E-cadherin, which misprocessing affects transcriptionally regulated genes downstream of E-cadherin, involved in cell adhesion [34]. Next to that, glutamate receptor proteolysis performed by γ-secretase complex was found to be crucial for synaptic transmission [35]. Furthermore, VEGF receptor proteolysis and phosphorylation controlled by presenilins were reported to be important for angiogenesis, what could have further consequences in damages of brain areas by interfering with oxygen and energy supply [36]. Presenilin substrates selection

different partners, which will be *described in detail in Section 6*.

liver, spleen, and kidney [15].

98 Senescence - Physiology or Pathology

provided in subsequent text.

**4. Presenilin biological functions**

Summarizing, presenilin biological functions and resultant interactome are not merely attributed to the γ-secretase activity and APP processing. Diversity of presenilin substrates is reflected by numerous biological implications including postsynaptic Ca2+ signalling, synaptogenesis, neurites outgrowth, lipid metabolism, cell adhesion, axon guidance, cell growth, regulation of dendritic spines, angiogenesis, LTP or glutamate synaptic transmission [30 (Tables 1 and 2), 38, 39]. In this regard, the amyloid cascade is complemented with the abovelisted processes disturbed in AD. Similarly, pathological ageing is manifested by a loss of protein homeostasis, DNA damage, lysosomal dysfunction, epigenetic changes, immune deregulation, or disturbed calcium homeostasis [6]. Altogether, AD and PA might result from presenilin-dependent processes or presenilins' interactomes.
