Abbreviations used:



Alzheimer’s disease


amyloid precursor protein


autophagic vacuoles

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that results in loss of memory, cognitive function, eventually leading to dementia. A key neuropathological event in AD is the cerebral accumulation of an ∼4 kDa peptide termed Aβ, the principal component of senile plaques. Amyloid plaques are formed of aggregates of amyloid-β-peptides, 37–43 amino-acid fragments (predominantly Aβ40 and Aβ42) derived by serial proteolysis of the amyloid precursor protein (APP) via β- and γ-secretases. β-Secretase has been identified as a novel membrane-tethered member of the aspartyl proteases, termed beta-site APP cleaving enzyme (BACE1) (Cole and Vassar 2008). APP proteolysis by β-secretase results in the production of secreted βAPP (βAPPs) along with membrane-associated C99 APP-C-terminal fragments (APP-C99), which serve as a substrate for γ-secretase resulting in the production of Aβ.

AD is a complex disease influenced by the actions of multiple genes, their interactions with one another and with the environment. In a small percentage (< 1%) of cases, AD is inherited as an autosomal dominant trait (familial AD); however, the majority of cases are sporadic. To date, the only strong genetic risk factor identified for sporadic AD is the inheritance of APOε4 allele. Clinical studies conducted in a large number of patients have shown that the most important risk factors for AD are aging and family history of the disease. However, evidence is accumulating that stroke and transient ischemic attacks significantly increase the risk of AD in elderly individuals (Reitz et al. 2011), indicating an additive or synergistic interaction between AD and cerebrovascular pathologies. Thus, stroke may represent either a precipitating or a triggering event in AD. Although there is an increasing body of knowledge indicating a strong association between cerebrovascular disease and AD, it remains unclear how cerebral ischemia leads to AD.

A candidate mechanism linking acute brain injuries to AD is Aβ deposition. APP has been shown to be up-regulated following ischemia both at transcriptional and protein levels and Aβ42 has been reported to increase in the brain and CSF following stroke (Kalaria 2000). More recently, BACE1 protein levels and β-secretase activity have been reported to increase in animal models of cerebral ischemia (Wen et al. 2004; Tesco et al. 2007; Hiltunen et al. 2009).

BACE1 is a stress-related protease that is also up-regulated in AD brains (Cole and Vassar 2008). We have previously reported that caspase activation elevates BACE1 levels and β-secretase activity owing to post-translational stabilization of BACE1 (Tesco et al. 2007). Using a rat ischemia model, we found that levels of golgi-associated, gamma adaptin ear containing, ARF binding protein 3 (GGA3), an adaptor molecule implicated in BACE1 trafficking, are reduced in a temporally coordinated manner with caspase activation and increases in BACE1 proteins levels. We established that caspase 3 cleaves GGA3 at several sites resulting not only in GGA3 depletion but also in the production of a dominant negative molecule. In cell-based studies, RNAi silencing of GGA3 directly led to increased BACE1 protein levels and β-secretase activity as evidenced by the enhanced APP-C99 and Aβ levels. Together, these data suggest a model in which apoptosis, e.g. induced by ischemia, drives the depletion of GGA3, which, in turn, leads to the stabilization of BACE1 and increased β-secretase activity. Decreased levels of GGA3 most likely engender an increase in BACE1 protein levels by interfering with the sorting of BACE1 to lysosomes where it is degraded (Kang et al. 2000; Koh et al. 2005).

In this issue of the journal, Zhang and colleagues provide interesting evidence suggesting that autophagy failure may play a role in the elevation of BACE1 and Aβ, and neuronal cell death observed in the thalamus between 7 and 14 days after focal cortical ischemia (Zhang et al. 2011). Autophagy is the major degradative pathway for organelles and proteins and its function is essential for neuronal survival. Accumulation of autophagic vacuoles (AV), as observed in AD and following cerebral ischemia, is a result of defective autophagy owing to increased AV induction or decreased AV clearance by lysosomes (Nixon and Yang 2011; Puyal et al. 2011). Autophagy failure can induce neuronal cell death directly or by activating apoptosis (Puyal et al. 2011). Although the accumulation of BACE1 and increased β-secretase activity in the thalamus following focal ischemia has been previously reported (Hiltunen et al. 2009), Zhang et al. 2011 show for the first time that BACE1 and APP/Aβ accumulate in AV in a pattern similar to that observed in AD (Nixon and Yang 2011). More importantly, treatment with 3-methyladenine (3-MA), an autophagy inhibitor, reduced the elevation of BACE1 and APP/Aβ, and thalamic neural damage. These findings support the hypothesis that inhibition of autophagy could be beneficial in preventing BACE1 and Aβ elevation after stroke. However, 3-MA treatment also reduces caspase 3 activation after ischemic insult (Puyal et al. 2011). Interestingly, Hiltunen et al. (2009) reported that GGA3 is depleted in association with BACE1 elevation in the thalamus 7–14 days after focal cerebral ischemia. Given that GGA3 depletion results in accumulation of BACE1 in early endosomes (Kang et al. 2000) and that the autophagosomes fuse with endosomes, caspase-mediate depletion of GGA3 can contribute to BACE1 accumulation in AV (Fig. 1). Thus, it is possible that 3-MA treatment restores BACE1 degradation by preventing caspase-mediated degradation of GGA3. The study by Zhang et al. 2011 raises the important question of whether defective autophagy produces BACE1 elevation by inducing apoptosis and/or by interfering with BACE1 lysosomal degradation (Fig. 1).


Figure 1.  Schematic representation of autophagic and apoptotic pathways leading to BACE1 elevation following cerebral ischemia.

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