Platelet Activation and Alzheimer’s Disease: The Probable Role of PI3K/AKT Pathway

BACKGROUND

Alzheimer’s disease is the most common neurodegenerative disorder, caused by loss of neurons and synapses in special regions of the central nervous system [1]. One of the main characterization factors of AD is accumulation of amyloid-β (Aβ) protein, which contributes to induce neuroinflammation, oxidative stress, and neuronal loss [2]. Different cells are involved in generation of Aβ, the most important one is neuron. Recently, the role of platelets in AD progression has been investigated due to the expression of factors that involved in Aβ production [3]. Alterations in different intracellular pathways during AD progression has been detected in several studies, which are identified as potential therapeutic targets. One of the most important of this pathway is the PI3K/AKT pathway, involved in different aspects of AD pathophysiology. On the other hand, this pathway plays a crucial role in activity of platelets. However, to the best of our knowledge, the association between the PI3K/AKT pathway and platelet activity and their correlation with AD pathophysiology has not been investigated and reported in the literature yet. This paper aims to present a hypothesis indicating the association between the PI3K/AKT pathway, platelet activity, and AD progression.

THE PI3K/AKT PATHWAY IN ALZHEIMER’S DISEASE

As the PI3K/AKT signaling pathway is known to be involved in the regulation of cell survival, its role in a wide range of diseases creation and progression has been investigated. Excessive activity of the PI3K/AKT pathway contributes to un-controlled cell proliferation, as demonstrated in cancer pathophysiology [4]. On the other hand, excessive suppression of this pathway may result in neuronal loss and progression of neurodegenerative diseases [5]. Regarding the isoforms of AKT, three isoforms of this kinase, namely AKT1, 2, and 3, are known which are expressed in different regions of the brain and its cell types. For instance, AKT1 and AKT3 are distributed throughout the hippocampus somatic layers, while AKT2 is mainly expressed in astrocytes but not in neurons of the hippocampus [6]. In recent years, the association between the PI3K/AKT pathway and AD has attracted much attention, and this pathway presented as a therapeutic target to inhibit AD progression [7]. One of the most interesting issues in the relation between the PI3K/AKT pathway and AD is its role in amyloid-β protein precursor (AβPP) processing and Aβ production and accumulation. There are two pathways to process AβPP, namely amyloidogenic and non-amyloidogenic pathways. In the amyloidogenic pathway, at the first step, AβPP is cleaved by the most known β-secretase enzyme, β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), leading to release the β-stubs. Remained fragment of AβPP in the cell membrane during the first step is affected by the other enzyme involved in Aβ processing, γ-secretase, leading to release of final form on Aβ. In the non-amyloidogenic pathway, α-secretases affect AβPP and caused to release AβPPα [8].

It is clearly understood that the PI3K/AKT pathway regulates the production of Aβ through regulation of different factors involved in amyloidogenic and non-amyloidogenic pathways. This pathway regulates the expression of AβPP and BACE-1 negatively, reduces Aβ production and exhibits protective effects against AD progression [9, 10]. On the other hand, this pathway enhances the expression and activity of ADAM10, one of the main α-secretases, leading to downregulate Aβ generation [11]. The association between the PI3K/AKT pathway and Aβ has led to introduce different agents as modulators of Aβ production. In this regard, it has been demonstrated that 7,8-Dithydroxycoumarin, a bioactive component of coumarin derived from Thymelaeaceae, induces the PI3K/AKT signaling pathway activation leading to increased ADAM10 expression and reduced BACE-1 levels in 5×FAD transgenic mice expressing human APP and PSEN1 with a total of five AD-linked mutations. This effect was shown to reduce Aβ production and mitigate synaptic loss and memory impairment [11]. Changes in activity of the PI3K/AKT pathway in different pathologies has been presented as a risk factor for developing cognitive impairment and presenting dementia in AD. In this regard, Liu and co-workers found that the PI3K/AKT pathway is altered in the autopsied frontal cortices from 10 type 2 diabetic patients (T2DM), nine AD, eight T2DM–AD, and seven control cases [12]. In this study, the PI3K/AKT pathway alterations have been introduced as a pathologic mechanism for increased AD risk in patients with diabetes. In addition, weighted burden analysis of exome-sequenced late-onset AD and controls cases revealed involvement of the PI3K/AKT in AD pathophysiology [13]. However, the main isoform of AKT involved in the pathophysiology of AD is not identified yet.

Collectively, alterations in the PI3K/AKT pathway increases the risk of AD progression, probably through dysregulation of Aβ production. This issue has led to introduce new therapeutics to activate this pathway to suppress AD development.

THE PI3K/AKT PATHWAY IN PLATELETS

Different isoforms of the Pi3K and AKT has been shown to be involved in regulation of platelet activity, in a way that activation of these kinases induce platelet activity and aggregation [14]. Different interventions to modulate the PI3K/AKT pathway and several mutations in their isoforms introduce the association between this pathway and platelet activity. In this regard, inhibition of the PI3K by specific inhibitors, PIK-75 and PI-103, has been shown that suppresses AKT activation, and leads to suppression of platelet activation [15, 16]. Pharmacologic inhibition of PI3Kα contributes to inhibition of insulin-like growth factor-1 (IGF-1)-induced AKT stimulation, suppression of platelet activation and thrombus formation in cultured human platelets [17]. In the other similar investigation, it was shown that PI3Kα inhibition augmented thrombopoietin-mediated platelet activation and thrombus formation via restricting thromboxane A2 synthesis and phosphorylation of the extracellular signal-regulated kinase (ERK) [18].

AKT as the main downstream target and effector of the PI3K has three isoforms, AKT1, 2, and 3 which their role in regulation of platelet activity has been shown in different studies [15]. For instance, it has been demonstrated that AKT1 KO mice prolonged the bleeding time, and impaired platelet aggregation, secretion, and spreading in response to different stimuli [19]. AKT2 KO platelets show diminished arterial thrombus generation, and it is required for activation and aggregation of integrin, and granule release induced by Gq induction by low doses of thrombin and TxA2 [20]. It has been proposed that AKT3 plays a central role in mediating of granule release and platelet aggregation induced by TxA2 and thrombin [21]. Additionally, AKT3 is responsible for glycogen synthase kinase-3 (GSK-3) suppression caused by thrombin, which contributes to arterial thrombosis in vivo [22, 23].

THE PI3K/AKT PATHWAY, PLATELETS, AND ALZHEIMER’S DISEASE

In recent years, platelets are introduced as important players in the pathophysiology of AD. Platelets are the primary source of AβPP in circulation can secrete a significant amount of Aβ followed by activation into the blood, which can be transported to the brain through the blood-brain barrier leading to promote Aβ deposition [24]. However, the exact mechanism of their involvement in AD is not clearly understood yet. As the PI3K/AKT signaling pathway plays a crucial role in both platelet activity and AD pathophysiology, it can be investigated as a main molecular mechanism in this regard. This pathway may be responsible for alterations in platelet activity during AD progression. Here we present a series of studies to clarify this issue. In this regard, the role of platelet activity in cognitive function should be examined. Recently, the results of an interesting study have been published which indicates the association between platelet activity and the risk of dementia during 20-year follow-up [25]. In addition, it has been demonstrated that patients with immune thrombocytopenic purpura exhibit several dementia-like symptoms, the most important of which are memory loss and cognitive impairment [26]. In another study, the expression of ADAM10 in platelets has been linked to cognitive function during aging process. In this study, it was reported that ADAM10 expression and enzymatic activity is increased along cognitively healthy aging [27].

To investigate the probable role of the PI3K/AKT pathway in platelet activity in AD, the expression and activity of targets of this pathway in AD patients’ platelet should be examined. In this regard, it has been demonstrated that the levels of ADAM10 in AD platelets is significantly reduced compared to controls [28]. Additionally, it has been reported that the activity of the levels of ADAM10 and the enzymatic activities of α- and β-secretase are altered in platelets of AD patients [29]. These alterations were shown to be in a way that induce amyloidogenic pathway and increase Aβ production. In another study, it was reported that the levels of BACE-1, AβPP, and presenilin-1 are increased along with reduced ADAM10 activity in platelets of chronic kidney disease (CKD) patient [30]. In this study, mentioned alterations introduced as markers for CKD associated cognitive dysfunction, and treatment with recombinant human erythropoietin (rHuEPO) presented as an effective neuroprotective agent in this context. Interestingly, in another clinical study it has been demonstrated that rHuEPO induces platelet activity through the PI3K phosphorylation [31], which may explain its role in inhibition of cognitive decline induced by CKD.

Collectively, reduced platelets activity and its association with AD risk may show altered activity of the PI3K/AKT pathway. On the other hand, alterations in factors involved in Aβ production are such that they could indicate excessive inhibition of this pathway in platelets.

In addition to mentioned points, it has been demonstrated that platelets are highly activated in AD patients [32]. These results do not reflect inconsistencies with the mentioned hypothesis. In explaining this issue, it can be paid to the differences in platelet activity in different stages of AD and their association with other factors involved in its pathophysiology. In this regard, the role of Aβ in activation of platelets can be investigated. It has been shown that Aβ induces platelet activation through enhance integrin αIIbβ3 activation [33]. This effect may be mediated by the PI3K/AKT pathway as it has been reported that Aβ induces the activation of this pathway [34], and on the other hand, the PI3K/AKT pathway is downstream effector of integrin αIIbβ3 [35]. However, in another study, it has been demonstrated that Aβ induces the PI3K/AKT signaling pathway activation through its effect on protease-activated receptors (PARs), leading to activate human platelets [36]. On the other hand, hyper-activation of platelets in AD patients has been linked to chronic inflammatory reaction that can mediate endothelial cell stress [37]. Although there is no study supporting this hypothesis in AD models, other models can be used to better understand it. In this case, it has been reported that binding of astrocyte-derived tumor necrosis factor-α (TNF-α), one of the main inflammatory cytokines involved in AD pathophysiology, to its receptor contributes to activation of platelets via activation of the PI3K/AKT pathway [38]. On the other hand, CD40, an overexpressed regulator of the peripheral immune response in AD brains, has been shown to be involved in astrocytes activation via the PI3K/AKT signaling pathway [39, 40]. However, more studies are required to identify the association between the PI3K/AKT pathway and neuroinflammation in platelets during AD progression.

CONCLUSION

Although platelets are often introduced as biomarkers to diagnose AD, their role in the pathophysiology of the disease is still unclear. Increased activity of various factors involved in the production of Aβ in platelets can be known as a reason to increase the production of this protein. Since all of these factors are controlled by the PI3K/AKT pathway, assessing the activity of this pathway in platelets in healthy individuals and AD patients can be helpful in identifying their role in AD pathophysiology. However, it seems that altered platelets activity followed by reduced activity of the PI3K/AKT during aging may lead to increase AD risk. On the other hand, in AD patients, elevated levels of Aβ and inflammatory mediators may induce platelets activity through activation of the PI3K/AKT pathway (Fig. 1). These issues can be very important in patients being treated with antiplatelet drugs or with thrombocytopenia. Also, designing studies to investigate the role of this pathway in platelets and its association with AD could help develop therapeutic targets to slow the progression of this disease.

OPEN IN VIEWER

Fig. 1

The association between the PI3K/AKT activity in platelets and AD risk. During aging, reduced activity of the PI3K/AKT pathway in platelets may be responsible for reduced ADAMs activity and increased BACE-1 and γ-secretase levels leading to increase Aβ production and deposition. This process may lead to induce cognitive dysfunction and increase AD risk. On the other hand, Aβ deposition and inflammatory mediators during AD progression may affect platelets leading to induce the PI3K/AKT pathway and subsequently increase platelet activity.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/22-0663r1).