The amyloid precursor protein (APP) has occupied a central position in Alzheimer’s disease (AD) pathophysiology, in large part due to the seminal role of amyloid-β peptide (Aβ), a proteolytic fragment derived from APP. Although the contribution of Aβ to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP’s involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPα, sAPPβ), various C- and N-terminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the –YENPTY– motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology.

Many central nervous system conditions that cause weakness, including many strokes, injure corticospinal tract but leave motor cortex intact. Little is known about the functional properties of surviving cortical regions in this setting, in part because many studies have used probes reliant on the corticospinal tract. We hypothesized that many features of motor cortex function would be preserved when assessed independent of the stroke-affected corticospinal tract. Functional MRI was used to study 11 patients with chronic hemiplegia after unilateral stroke that spared regions of motor cortex. Activation in stroke-affected hemisphere was evaluated using 3 probes independent of affected corticospinal tract: passive finger movement, a hand-related visuomotor stimulus, and tapping by the nonstroke index finger. The site and magnitude of cortical activation were similar when comparing the stroke hemisphere to findings in 19 control subjects. Patients activated each of 8 cortical regions with similar frequency as compared to controls, generally with a smaller activation volume. In some cases, clinical measures correlated with the size or the site of stroke hemisphere activation. The results suggest that, despite stroke producing contralateral hemiplegia, surviving regions of motor cortex actively participate in the same proprioceptive, visuomotor, and bilateral movement control processes seen in control subjects.

Highlights d Ab-dependent caspase activation cleaves the APP C terminus, leading to synaptic injury d Inhibition of APP C-terminal cleavage ameliorates Ab-dependent synaptic injury d APP D664A mutation prevents APP C terminus cleavage and impairs caspase activation

Summary:This study aimed to characterize brain activation and perfusion early after stroke within cortical regions that would later change activation during recovery. Patients were studied serially after stroke (mean t 1 , ‫ס‬ 16 days after stroke, t 2 ‫ס‬ 3.5 months later) using perfusion-weighted imaging and functional magnetic resonance imaging during finger movement. Controls (n ‫ס‬ 7) showed no significant change in regional activation volumes over time. Among stroke patients (n ‫ס‬ 8), however, recovery was accompanied by several patterns of functional magnetic resonance imaging change, with increased activation volumes over time in five patients and decreased in two. Most regions increasing activation over time were in the stroke hemisphere. Of the five patients showing increased activation over time, specific activation foci enlarged at t 2 were already activated at t 1 in four patients, and at least one focus growing from t 1 to t 2 was in a different arterial distribution from the infarct in all five patients. Perfusion of sensorimotor cortex at t 1 was generally not reduced in the stroke hemisphere (94% of noninfarcted hemisphere). Improved clinical outcome was related to increased activation within sensory cortices of both brain sides, including bilateral secondary somatosensory areas. Early after stroke, cortical activation that will later increase in parallel with recovery is often already identifiable, can be remote from the vascular territory of the infarct, and is not likely hindered by reduced perfusion. The findings may be useful for restorative interventions introduced during the weeks after a stroke. Key Words: Cerebral blood flow-Stroke recovery-Plasticity-Functional MRI brain mapping.Most patients show clinical improvement in the weeks to months after a stroke. Human brain mapping studies performed serially during this recovery period have described increased activity in a number of regions that are structurally intact. Many of these changes arise in parallel with behavioral improvement and thus may reflect restorative events. Such events can be amplified by a range of exogenous treatments (Chen et al., 2001;Kawamata et al., 1997;Ren et al., 2000;Stroemer et al., 1998) and are therefore logical targets for human studies.The current study performed serial functional magnetic resonance imaging (fMRI) evaluation of stroke patients to address two questions regarding brain function early after stroke. Functional MRI was first performed approximately 2 weeks after stroke, a time (Duncan et al., 1992(Duncan et al., , 2000Nakayama et al., 1994) before motor function generally returns. This fMRI scan was supplemented by measurement of CBF. Functional MRI was then repeated approximately 3 months later.The first question evaluated in this study was whether activation was present 2 weeks after stroke in those brain regions that would later increase function in parallel with behavioral recovery. If so, this finding would suggest that therapeutic targets relevant to recovery might be identifiable at ear...

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