Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer disease patients.

Abstract

The amyloid 13-protein is deposited in senile plaques and the cerebrovasculature in Alzheimer disease (AD). Since it is derived from proteolytic processing of its parent protein, the amyloid 13-protein precursor (APP), we investigated whether levels of the secreted forms of APP are altered in cerebrospinal fluid (CSF) of AD patients. Quantitative immunoblotting studies with the anti-APP monoclonal antibody P2-1 revealed that probable AD patients had markedly lower CSF APP levels than did demented non-Alzheimer-type patients and healthy control subjects. Using antibody P2-1 in an enzyme-linked immunosorbent assay, we measured CSF levels of APP in a larger population consisting of 13 patients diagnosed with probable AD, 18 patients diagnosed with dementia (non-Alzheimer type), and 16 nondemented, healthy controls.Mean CSF levels of APP were =3.5-fold lower in the live patients diagnosed with probable AD compared to the demented non-Alzheimer-type controls or the nondemented, healthy individuals. These findings suggest that abnormal metabolism of APP is reflected in the extracellular fluids of the central nervous system and that CSF levels of soluble APP provide a useful biochemical marker to assist in the clinical diagnosis of AD.Alzheimer disease (AD) leads to a progressive and irreversible loss of memory and cognitive function in afflicted elderly individuals. One study has suggested that the disease afflicts as many as 4 million people in the United States alone (1). The hallmark event of AD is deposition of the amyloid }3-protein in senile plaques within brain parenchyma and in cerebral vessel walls of afflicted individuals (2-6). The amyloid (3-protein is a 4.2-kDa peptide proteolytically derived from a large precursor protein designated the amyloid 13-protein precursor (APP) (7-10). APPs can be translated from at least three alternatively spliced mRNAs, two of which contain an additional insert that encodes a domain homologous to Kunitztype serine protease inhibitors (11-13). The secreted form of APP that contains the Kunitz inhibitor domain is identical to the previously described protease inhibitor protease nexin 2 (PN-2) (14, 15). Soluble derivatives of APP are present in brain and cerebrospinal fluid (CSF), suggesting a normal function in the central nervous system (14,(16)(17)(18)(19)(20). Recent studies have suggested that abnormal proteolytic processing of APP leads to formation of the amyloid (3-protein (21-23), which in turn may contribute to the pathology of AD. Abnormal proteolysis associated with AD may, therefore, lead to altered levels of APP in the central nervous system.Previous studies suggested that CSF levels of secreted forms of APP were higher in AD patients than in control subjects (16,19,20). On the other hand, more recent reports indicated that the amounts of secreted APP in CSF were slightly decreased in AD patients (24-26). However, the measurements in those studies employed various antibodies prepared against synthetic peptides or expression products corresponding to variou...

Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone

“…This supports the view that SVZ neurogenesis is similarly regulated in all mammals. In the light of the reduction in sAPP concentrations in brains from individuals with AD (Lannfelt et al, 1995;Van Nostrand et al, 1992), the present data that link sAPP levels and the number of SVZ progenitors, suggest that a deficit in neurogenesis could play a role in some aspects of AD pathogenesis. Interestingly, individuals with AD show very early odor discrimination defects (Nordin and Murphy, 1998) as do mutant mice with reduced SVZ neurogenesis (Gheusi et al, 2000).…”

“…These growth-promoting properties, together with its structural similarities with cysteine-rich growth factors (Rossjohn et al, 1999), suggest that sAPP may function as a growth factor in vivo. Interestingly, infusion of sAPP into the brain increases synaptic density and improves memory retention (Meziane et al, 1998;Roch et al, 1994) and levels of sAPP are decreased in the CSF of individuals with AD (Lannfelt et al, 1995;Van Nostrand et al, 1992). Moreover, sAPP stimulates proliferation of neural stem cells isolated from the embryonic brain (Hayashi et al, 1994;Ohsawa et al, 1999).…”

Recent research on the causes of Alzheimer's disease

“…brain capillary endothelial cells and circulating blood cells) tissue to the plaques is still subject to debate. The discovery that there is a marked reduction in APP levels in the cerebrospinal fluid of Alzheimer's disease patients (Van Nostrand et al 1992) lends strong support to the idea that abnormal APP metabolism is fundamental to the disease. The possibility that fragments other than p-amyloid may be neurotoxic or contribute to the overall progress of the disease is only beginning to be investigated.…”

Cerebrospinal fluid and blood biomarkers in Alzheimer’s disease

“…Quantification of different Aβ forms in CSF can be determined by specific ELISAs [44] . Early studies reported controversial results involving total Aβ measurements in CSF [45][46][47] . Later, several reports demonstrated no changes in Aβ1-40 CSF levels.…”

“…BACE cleaves APP and releases a large N-terminal fragment (sAPPβ). The membrane-anchored frag- [73,75] Decreased [65] β-amyloid (Aβ) Decreased [45,46] No difference [79][80][81][82] No difference [47] Aβ1- 40 No difference [24] No difference [83] Increased [84] Decreased [85] Aβ1- 42 Decreased [24] Increased [83] -Aβ1-42/Aβ1-40 ratio Decreased [48] No difference [83] Decreased [78,84,86] APP ratio --Decreased [90][91][92][93] Ubiquitin Increased [24] No difference [148] BACE1 Increased [67] --Cholesterol -Decreased [94,95] Increased [96][97][98] 24S-hydroxycholesterol Increased [102] No difference [103] Decreased [104] Homocysteine -Increased [106,107,109] Epidermal growth factor -Decreased [111] Decreased [93] Increased [112] Glial cell line-derived growth factor -Decreased [111] No difference …”