Treatments for neurotoxicity in Alzheimer's disease...

Details Treatments for neurotoxicity in Alzheimer's disease... Treatments for neurotoxicity in Alzheimer's disease...

1998-01-09

2001-01-09

Celsa, Bennett (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S013800, C514S014800, C514S015800, C514S016700, C530S325000, C530S326000, C530S327000, C530S328000, C530S329000, C530S330000

Reexamination Certificate

active

06172043

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to compounds which antagonize the neurotoxic effects of &bgr;-amyloid peptide aggregates, methods for using such compounds and methods for discovering compounds which also antagonize the neurotoxic effects of &bgr;-amyloid peptide aggregates.
BACKGROUND OF THE INVENTION
The post-mortem pathology of Alzheimer's Disease is characterized by the presence in particular regions of the brain of many extracellular plaques and of many intracellular neurofibrillary tangles, whose density correlates with the severity of dementia. There is also massive, but regional, neuronal cell disfunction and cell loss, caused presumably by the reported neurotoxicity of the &bgr;-amyloid peptides which are components of senile plaques. The cytotoxicity of the &bgr;-amyloid peptides was first established in primary cell cultures from rodent brains and also in human cell cultures. These were relatively long-term experiments, lasting for a few days. The immediate molecular cause of the cytotoxicity was not clear from these reports. The work of Mattson et al. (
J Neurosci.
12:376-389, 1992) indicates that &bgr;-amyloid peptides, including the sequence &bgr;AP
25-35
, in the presence of the excitatory neurotransmitter glutamate causes an immediate increase in intracellular calcium, which, it is supposed, is very toxic to the cell through its greatly increased second messenger activities.
The formation of pathological &bgr;-amyloid peptides in Alzheimer's Disease is not well understood. The amyloid precursor protein (APP) is a very large transmembrane protein whose normal turnover degradation cleaves the presumptive &bgr;-amyloid peptide in the middle, thus making it inactive as a neurotoxic agent. In addition, the future C-terminus of &bgr;-amyloid peptides is buried in the middle of the lipid membrane. How the degradation of APP is altered in Alzheimer's Disease (AD) is only gradually becoming clear with no convincing explanation at present.
There are three &bgr;-amyloid peptides, &bgr;AP
1-42
, &bgr;AP
1-40
, and &bgr;AP
25-35
, which are homologous to the tachykinin neuropeptides. All three peptides are strongly neurotoxic when applied to cultured cells. &bgr;AP
1-40
and &bgr;AP
1-42
are the most prominent components of senile plaques. It is not clear whether &bgr;AP
25-35
occurs in the brains of AD individuals. &bgr;AP
25-35
might be absent because it has been scavenged when dead neurons are removed.
The &bgr;AP
1-42
peptide, and related shorter peptides, are cytotoxic towards cultured neuronal cells at micromolar concentrations, but neurotrophic at nanomolar concentrations. Others have observed that the peptide is cytotoxic also in vivo. Variability in results from different laboratories perhaps can be ascribed to the different propensities of particular &bgr;-amyloid peptides to aggregate in aqueous solution. It has been suggested that long-term cytotoxicity resides in insoluble aggregates. The molecular mechanism of this cytotoxicity is not well known, perhaps because most of the reported experiments examine chronic cytotoxic effects only after 24-48 hours of exposure to insoluble aggregates of &bgr;-amyloid peptides.
The ability of &bgr;-amyloid peptides such as &bgr;AP
1-40
to form cation-selective ionophores was postulated earlier as a mechanism for cytotoxicity (Arispe et al.,
Proc. Nat'l Acad. Sci. USA
90:10573-10577, 1993; Arispe et al.,
Proc. Nat'l Acad Sci. USA
90:567-571, 1993). However, these experiments were carried out in artificial membranes. While in actual cells the ionophore mechanism might indeed be an important factor, there are at least two other mechanisms: interaction between the &bgr;-amyloid peptides with existing ion channels, and penetration of the peptides into the cell with consequent release of calcium from internal stores.
Thus, while the precise mechanism of neurotoxicity of &bgr;-amyloid peptides in Alzheimer's Disease has not been definitively established, there is a need to determine which of the aforementioned mechanisms of cytotoxicity is the cause of neuronal cell death in AD. Identification of the cytotoxic mechanism is needed to enhance the prospects of designing compounds capable of antagonizing the effects of aggregation of &bgr;-amyloid peptides.
SUMMARY OF THE INVENTION
The invention involves in one aspect identification of a mechanism of &bgr;-amyloid peptide cytotoxicity, which enables treatment of conditions caused by &bgr;-amyloid peptide aggregates by administration of compounds which antagonize the mechanism of cytotoxicity. The invention involves in another aspect the identification and isolation of peptides which can antagonize the aggregation of &bgr;-amyloid peptides and the neurotoxic effects of such aggregates. The isolated peptides include decoy peptides which were selected for their ability to form a complex with &bgr;AP
25-35
, or are derived from peptides so selected. The decoy peptides have considerable &bgr;-sheet forming potential. Decoy peptides associate with the multimer-forming &bgr;-amyloid peptide and either block the usual aggregation or are incorporated into the multimer peptide (aggregate) to make it inactive. The invention further involves the use of such compounds in the preparation of a medicament for preventing cytotoxicity resulting from &bgr;-amyloid peptide aggregation.
According to another aspect of the invention, a composition is provided. The composition includes a decoy peptide which binds to a neurotoxic &bgr;-amyloid peptide and reduces the ability of the neurotoxic &bgr;-amyloid peptide to form aggregates which increase calcium influx into neuronal cells, preferably NT2-N cells differentiated with retinoic acid. Preferably the decoy peptide is non-hydrolyzable, particularly a decoy peptide selected from the group consisting of peptides comprising D-amino acids, peptides comprising a —psi[CH
2
NH]— reduced amide peptide bond, peptides comprising a —psi[COCH
2
]— ketomethylene peptide bond, peptides comprising a —psi[CH(CN)NH]— (cyanomethylene)amino peptide bond, peptides comprising a —psi[CH
2
CH(OH)]— hydroxyethylene peptide bond, peptides comprising a —psi[CH
2
O]— peptide bond, and peptides comprising a —psi[CH
2
S]— thiomethylene peptide bond. In other embodiments, the decoy peptide binds to a neurotoxic &bgr;-amyloid peptide is selected from the group consisting of &bgr;AP
1-42
and &bgr;AP
25-35
. Preferably, the decoy peptide has &bgr;-sheet forming potential, and is between 4 and 20 amino acids in length. More preferably, the decoy peptide is between 5 and 10 amino acids in length. Optionally, the decoy peptide can be a cyclized peptide.
In certain preferred embodiments, the decoy peptide comprises a sequence selected from the group consisting of amino acids 1-6 of SEQ ID NO: 1, amino acids 1-6 of SEQ ID NO:2, amino acids 1-6 of SEQ ID NO:3, amino acids 1-6 of SEQ ID NO:4, amino acids 1-6 of SEQ ID NO:5, amino acids 1-6 of SEQ ID NO:6, amino acids 1-6 of SEQ ID NO:7, amino acids 1-6 of SEQ ID NO:8, amino acids 1-9 of SEQ ID NO:9, amino acids 1-7 of SEQ ID NO:12, amino acids 1-7 of SEQ ID NO: 13, amino acids 1-7 of SEQ ID NO: 14, amino acids 1-6 of SEQ ID NO: 15, amino acids 1-5 of SEQ ID NO:16, amino acids 1-9 of SEQ ID NO: 17, amino acids 1-9 of SEQ ID NO:18, amino acids 1-7 of SEQ ID NO:19, amino acids 1-5 of SEQ ID NO:21, amino acids 1-5 of SEQ ID NO:22, amino acids 1-5 of SEQ ID NO:23, amino acids 1-5 of SEQ ID NO:24, amino acids 1-5 of SEQ ID NO:25, amino acids 1-5 of SEQ ID NO:26, amino acids 1-5 of SEQ ID NO:27, amino acids 1-6 of SEQ ID NO:28, amino acids 1-6 of SEQ ID NO:29, and amino acids 1-6 of SEQ ID NO:30. In particularly preferred embodiments, the the decoy peptide comprises a sequence selected from the group consisting of amino acids 1-6 of SEQ ID NO:2, amino acids 1-6 of SEQ ID NO:9 and amino acids 1-9 of SEQ ID NO: 17.
According to another aspect of the invention, the decoy peptides of the invention are conjugated to a compound which facilitates tr

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